Substituted phenylsulfur trifluoride and other like fluorinating agents

ABSTRACT

Novel substituted phenylsulfur trifluorides that act as fluorinating agents are disclosed. Also disclosed are methods for their preparation and methods for their use in introducing one or more fluorine atoms into target substrate compounds. Finally, various intermediate compounds for use in preparing substituted phenylsulfur trifluorides are provided.

RELATED APPLICATION

This application claims priority to U.S. patent application Ser. No.12/106,460, entitled “Substituted Phenylsulfur Trifluoride and OtherLike Fluorinating Agents,” filed Apr. 21, 2008, U.S. patent applicationSer. No. 11/828,162 entitled “Substituted Phenylsulfur Trifluoride andOther Like Fluorinating Agents,” filed Jul. 25, 2007, U.S. patentapplication Ser. No. 11/494,983 entitled “Substituted PhenylsulfurTrifluoride and Other Like Fluorinating Agents,” filed Jul. 28, 2006,the disclosures of which are hereby incorporated by reference in theirentirety.

TECHNICAL FIELD

The present invention relates to fluorinating agents and moreparticularly to novel substituted phenylsulfur trifluorides that act asfluorinating agents.

BACKGROUND OF THE INVENTION

Fluorine-containing compounds have found wide use in medical,agricultural, electronic materials and other like industries (seeChemical & Engineering News, June 5, pp 15-32 (2006); Angew. Chem. Ind.Ed., Vol. 39, pp 4216-4235 (2000)). These compounds show specificbiologic activity or physical properties based on the presence of one ormore fluorine atoms. A particular drawback in their usefulness is thescarcity of natural fluorine-containing compounds, requiring most suchcompounds to be prepared through organic synthesis.

Fluorinating agents are compounds that selectively introduce fluorineatom(s) into target compounds through one or more chemical reactions toproduce fluorine-containing compounds. Particularly useful fluorinatingagents have the capacity to replace oxygen or oxygen-containing groupsin the target compound with fluorine. A number of fluorinating agentshave been discovered; however, as discussed in more detail below, all ofthese agents have significant drawbacks based on safety, reactivity,storage stability, and/or disposability.

Illustrative examples of known fluorinating agents include: sulfurtetrafluoride (SF₄), a highly toxic gas that is often utilized underpressure [J. Am. Chem. Soc., Vol. 82, pp 543-551 (1960)];N,N-diethylaminosulfur trifluoride (DAST), an unstable liquid agenthaving a highly explosive nature, i.e., low thermal stability and largeamounts of thermal energy upon decomposition [J. Org. Chem., Vol. 40, pp574-578 (1975) and Chem. & Eng. News, Vol. 57, No. 19, p 4 (1979)];bis(methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor®) a product havinggreater thermal stability than DAST but still having a startingdecomposition temperature similar to DAST [Chemical Communications, pp215-216 (1999)]; selenium tetrafluoride (SeF₄), a highly toxic seleniumcompound [J. Am. Chem. Soc., Vol. 96, pp 925-927 (1974)]; and variousother more designed fluorinating agents that provide greater safety buthave provided substantially reduced reactivity and yields:phenylfluorophosphane reagents [Ph_(n)PF_(5-n) (n=1˜3), Chem. Pharm.Bull., Vol. 16, p 1009 (1968)], α,α-difluoroalkylamino reagents[ClCFHCF₂NEt₂, Organic Reactions, Vol. 21, pp 158-173 (1974);CF₃CFHCF₂NEt₂, Bull. Chem. Soc. Jpn, Vol. 52, pp 3377-3380 (1979);CF₂HCF₂NMe₂, J. Fluorine Chem., Vol. 109, pp 25-31 (2001)],2,2-difluoro-1,3-dimethylimidazolidine [Jpn. Kokai Tokkyo Koho JP 200038,370; Chemical Communications, pp 1618-1619 (2002)], and[(m-methylphenyl)difluoromethyl]diethylamine (Tetrahedron, Vol. 60, pp6923-6930).

In addition, phenylsulfur trifluoride has also been synthesized and usedas a fluorinating agent, but its fluorination yields have proven low andits applicability is narrow [J. Am. Chem. Soc., Vol. 84, pp 3058-3063(1962); Acta Chimica Sinica, Vol. 39, No. 1, pp 63-68 (1981); and seeComparison Example 1 in Table 5]. Pentafluorophenylsulfur trifluoridewas also synthesized and used as a fluorinating agent, but has provencostly, since its starting material is expensive and it has only tworeactive fluorine atoms out of eight existing in the molecule [J.Fluorine Chem., Vol. 2, pp 53-62 (1972/73)]. More recently,p-nitrophenylsulfur trifluoride was examined and also shown to havelittle or no fluorination ability [Acta Chimica Sinica, Vol. 39, No. 1,pp 63-68 (1981)].

Each of these conventional illustrative fluorinating agents requiresroom for improvement on providing more effective and safer reagents foruse in the production of these important fluorine-containing compounds.

As such, there is a need in the field to provide safe, reactive, lesshazardous, cost effective, fluorinating agents, especially fluorinatingagents that selectively introduce fluorine atoms into compounds byreplacement of oxygen or oxygen-containing groups with fluorine atoms.Ideally, these fluorinating agents provide high yields and can behandled and stored in a safe manner.

The present invention is directed toward overcoming one or more of theproblems discussed above.

SUMMARY OF THE INVENTION

The present invention provides novel fluorinating agents for use in theintroduction of fluorine atoms into target compounds. The resultanttarget compounds, i.e., fluorine-containing compounds, have been shownto have tremendous potential in medical, agricultural, electronicmaterials' and other like uses.

In general, fluorinating agents of the invention are novel substitutedphenylsulfur trifluoride compounds. The substituted phenylsulfurtrifluoride compounds are shown herein to have substantial functionaland safety benefits over conventional fluorinating agents.

The present invention also provides new intermediate compounds for usein the synthesis of the novel substituted phenylsulfur trifluorides.

Finally, the present invention provides synthesis schemes for the novelcompounds of the invention, and data illustrating the use of theseagents in preparing various fluorine-containing compounds.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel fluorinating agents for use inintroducing fluorine atoms into target compounds. In the presentinvention the term “target compound” includes any substrate that oncefluorinated is useful in the medical, agricultural, biological,electronic materials' or other like field, i.e., is afluorine-containing compound. In preferred instances, the targetcompound(s) of the invention include one or more oxygen atom(s) and/orone or more oxygen-containing group(s), and/or one or more sulfuratom(s) and/or one or more sulfur-containing group(s) for selectivereplacement by the fluorine atom(s). Illustrative target compoundsinclude alcohols, aldehydes, ketones, carboxylic acids, acid halides,esters, acid anhydrides, amides, imides, epoxides, lactones, lactams,sulfonic acids, sulfinic acids, sulfenic acids, thiols, sulfides,sulfoxides, thioketones, thioesters, dithioesters, thiocarboxylic acids,dithiocarboxylic acids, thiocarbonates, dithiocarbonates,trithiocarbonates, thioketals, dithioketals, thioacetals, dithioacetals,thioamides, thiocarbamates, dithiocarbamates, orthothioesters,phosphines, phosphine oxides, phosphine sulfides, and phosphonic acids.

Embodiments of the invention include novel substituted phenylsulfurtrifluorides. Novel substituted phenylsulfur trifluorides are shownherein to be potent agents for selectively introducing fluorine atomsinto target compounds thereby producing fluorine-containing compounds.

Fluorinating agents of the present invention show high thermalstability, having high decomposition temperatures and low exothermicheat (−ΔH) values as compared to the conventional useful agents, DASTand Deoxy-Fluor® (see Examples below). In addition, fluorinating agentsof the invention are highly reactive with a number of different targetcompounds, typically providing high yields of fluorine-containingproduct compounds. Although the known compounds, phenylsulfurtrifluoride (PhSF₃) and p-methylphenylsulfur trifluoride (p-CH₃C₆H₄SF₃)(J. Am. Chem. Soc., Vol. 84, pp 3058-3063 (1962)) have highdecomposition temperatures, they have high exothermic heat and theirfluorination reactivity is low (see Examples below). The high stabilityand reactivity of the present invention's compounds is unexpected whencompared to those of conventional fluorinating agents, i.e., DAST,Deoxo-Fluor®, PhSF₃, and the like.

Embodiments of the invention also provide methods for preparing thefluorinating agents and for using the fluorinating agents in thepreparation of fluorine-containing compounds.

The invention provides compounds of the formula (I):

in which

R^(1a) and R^(1b) can independently be a hydrogen atom; a primary orsecondary alkyl group having from one to eight carbon atoms; or aprimary, secondary, or tertiary alkyl group having one to eight carbonatoms and at least one ether linkage;

R^(2a), R^(2b), and R³ are independently a hydrogen atom; a halogenatom; a primary, secondary, or tertiary alkyl group having from one toeight carbon atoms; or a primary, secondary, or tertiary alkyl grouphaving one to eight carbon atoms and at least one ether linkage;

provided that, when R³ is a hydrogen atom, at least two of R^(1a),R^(1b), R^(2a), and R^(2b) each is independently a halogen atom; aprimary, secondary, or tertiary alkyl group having from one to eightcarbon atoms; or a primary, secondary, or tertiary alkyl group havingtwo to eight carbon atoms and at least one ether linkage; or, at leastone of R^(1a), R^(1b), R^(2a), and R^(2b) is a primary, secondary, ortertiary alkyl group having two to eight carbon atoms and at least oneether linkage.

Further, when R³ is a primary alkyl group having one to eight carbonatoms, at least one of R^(1a), R^(1b), R^(2a), and R^(2b) is a halogenatom; a primary, secondary, or tertiary alkyl group having from one toeight carbon atoms; or a primary, secondary, or tertiary alkyl grouphaving two to eight carbon atoms and at least one ether linkage; and

when at least two of R^(2a), R^(2b), and R³ are tertiary alkyl groups,the tertiary alkyl groups are non-adjacent.

In preferred embodiments of formula (I), the alkyl groups have from oneto four carbon atoms, and the alkyl groups having an ether linkage(s)have from two to five carbon atoms. More preferred alkyl groups of R³are tertiary alkyl groups, and most preferred alkyl group of R³ istert-butyl group.

Some embodiments of the invention are those compounds of formula (I)where primary or secondary alkyl groups of R^(1a) and R^(1b) having fromone to eight carbon atoms, include: primary alkyl groups such as CH₃,CH₂CH₃, CH₂(CH₂)_(n)CH₃ (n=1-6), CH₂CH(CH₃)₂, and CH₂C(CH₃)₃, andsecondary alkyl groups such as CH(CH₃)₂, CH(CH₃)CH₂CH₃, andCH(CH₃)CH₂(CH₂)_(n)CH₃ (n=1-4). More preferred primary or secondaryalkyl groups of R^(1a) and R^(1b) include: CH₃, CH₂CH₃, CH₂(CH₂)_(n)CH₃(n=1 or 2), CH₂CH(CH₃)CH₃, and CH(CH₃)₂, and, most preferred primary orsecondary alkyl groups are CH₃ and CH(CH₃)₂.

Other embodiments of the invention are those fluorinating agents whereprimary, secondary, or tertiary alkyl groups having from one to eightcarbon atoms of R^(2a) and R^(2b) include: primary alkyl groups such asCH₃, CH₂CH₃, CH₂(CH₂)_(n)CH₃ (n=1-6), CH₂CH(CH₃)₂, and CH₂C(CH₃)₃,secondary alkyl groups such as CH(CH₃)₂, CH(CH₃)CH₂CH₃,CH(CH₃)CH₂(CH₂)_(n)CH₃ (n=1-4), and tertiary alkyl groups such asC(CH₃)₃, C(CH₃)₂CH₂CH₃, and C(CH₃)₂CH₂(CH₂)_(n)CH₃ (n=1-3). Morepreferred primary, secondary, or tertiary alkyl groups having from oneto eight carbon atoms of R^(2a) and R^(2b) include: CH₃, CH₂CH₃,CH₂(CH₂)_(n)CH₃ (n=1, 2), CH₂CH(CH₃)₂, CH(CH₃)₂, CH(CH₃)CH₂CH₃, andC(CH₃)₃, and most preferred primary, secondary, or tertiary alkyl groupsare CH₃, CH(CH₃)₂, and C(CH₃)₃.

Other embodiments of the invention are those fluorinating agents whereprimary, secondary, or tertiary alkyl groups of R³ having from one toeight carbon atoms, include: primary alkyl groups such as CH₃, CH₂CH₃,CH₂(CH₂)_(n)CH₃ (n=1-6), CH₂CH(CH₃)₂, and CH₂C(CH₃)₃, secondary alkylgroups such as CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH(CH₃)CH₂(CH₂)_(n)CH₃ (n=1-4),and tertiary alkyl groups such as C(CH₃)₃, C(CH₃)₂CH₂CH₃, andC(CH₃)₂CH₂(CH₂)_(n)CH₃ (n=1-3). More preferred primary, secondary, ortertiary alkyl groups of R³ having from one to eight carbon atomsinclude: CH₃, CH₂CH₃, CH₂(CH₂)_(n)CH₃ (n=1, 2), CH₂CH(CH₃)₂, CH(CH₃)₂,CH(CH₃)CH₂CH₃, and C(CH₃)₃, and most preferred primary, secondary, ortertiary groups of R³ are CH₃, CH(CH₃)₂, and C(CH₃)₃.

Some embodiments of the invention are those compounds of formula (I)where primary, secondary, or tertiary alkyl groups of R^(1a), R^(1b),R^(2a), R^(2b), and R³ having from two to eight carbon atoms and atleast one ether linkage include: primary alkyl groups such as CH₂OCH₃,CH₂OCH₂CH₃, CH₂OCH₂(CH₂)_(n)CH₃ (n=1-5), CH₂OCH(CH₃)₂,CH₂OCH(CH₃)CH₂CH₃, CH₂OCH₂CH(CH₃)₂, CH₂OC(CH₃)₃, CH₂CH₂OCH₃,CH₂CH₂OCH₂CH₂OCH₃, CH₂O(CH₂CH₂O)_(n)CH₂CH₃ (n=1, 2),CH₂O(CH₂CH₂O)_(n)CH₃ (n=1-3), CH₂O(CH₂CH₂CH₂O)_(n)CH₃ (n=1, 2),CH₂O[CH(CH₃)CH₂O]_(n)CH₃ (n=1, 2), and CH₂O[CH₂CH(CH₃)O]_(n)CH₃ (n=1,2); secondary alkyl groups such as CH(CH₃)OCH₃, CH(CH₃)OCH₂CH₃, andCH(CH₃)CH₂OCH₃; and tertiary alkyl groups such as C(CH₃)₂OCH₃,C(CH₃)₂OCH₂CH₃, and C(CH₃)₂CH₂OCH₃. More preferred primary, secondary ortertiary alkyl groups of R^(1a), R^(1b), R^(2a), R^(2b), and R³ havingat least one ether linkage include: CH₂OCH₃, CH₂OCH₂CH₃, CH₂OCH₂CH₂CH₃,CH₂OCH(CH₃)₂, CH₂OCH₂(CH₂)₂CH₃, CH₂OCH(CH₃)CH₂CH₃, CH₂OCH₂CH(CH₃)₂,CH₂OC(CH₃)₃, CH₂OCH₂C(CH₃)₃, CH₂OCH₂CH₂OCH₃, CH₂OCH₂CH₂OCH₂CH₃,CH₂OCH₂CH₂CH₂OCH₃, CH₂CH₂OCH₃, CH₂CH₂OCH₂CH₃, CH₂CH₂OCH(CH₃)₂,CH₂CH₂OCH₂CH₂OCH₃, CH(CH₃)OCH₃, CH(CH₃)OCH₂CH₃, C(CH₃)₂OCH₃, andC(CH₃)₂OCH₂CH₃, and the most preferred alkyl groups having at least oneether linkage are CH₂OCH₃, CH₂OCH₂CH₃, CH₂OCH(CH₃)₂, andCH₂OCH₂CH(CH₃)₂.

When used herein, the term “halogen atom” or “halo” include fluorine,chlorine, bromine and iodine and fluoro, chloro, bromo, and iodo,respectively.

Examples of preferred halogen atoms of R^(2a), R^(2b), and R³ include:fluorine, chlorine, bromine or iodine atoms, among these halogen types,fluorine, chlorine or bromine are more preferred, fluorine and chlorineare furthermore preferred, and chlorine is most preferred.

When used herein, the term “alkyl” includes all straight and branchedisomers. Representative examples of alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, and octyl. Alkyl mayinclude an alkyl substituted with a chlorine atoms(s) and/or a fluorineatom(s) such as CH₂Cl and CH₂F.

When used herein, the term “ether linkage” is carbon atom-oxygenatom-carbon atom bonding (C—O—C).

Table 1 provides illustrative combinations of R^(1a), R^(1b), R^(2a),R^(2b) and R³ for inclusion in formula (I).

TABLE 1 Illustrative Examples of Substituted Phenylsulfur TrifluorideCompounds of Formula (I) Showing R^(1a), R^(1b), R^(2a), R^(2b), and R³Combinations Based On Substitutions Into Formula (I) R^(1a) R^(1b)R^(2a) R^(2b) R³ H H H H C(CH₃)₃ H H H H C(CH₃)₂CH₂CH₃ H H H HC(CH₃)₂(CH₂)₂CH₃ H H H H C(CH₃)₂(CH₂)₃CH₃ H H H H C(CH₃)₂(CH₂)₄CH₃ H HC(CH₃)₃ C(CH₃)₃ H CH₃ H H H C(CH₃)₃ CH₃ CH₃ H H C(CH₃)₃ CH₃ CH₃ H HCH(CH₃)CH₂CH₃ CH₃ CH₃ H H CH₂CH(CH₃)₂ CH₃ CH₃ H H CH₂(CH₃)₂CH₃ CH₃ CH₃ HH CH₂CH₂CH₃ CH₃ CH₃ H H C₂H₅ C₂H₅ C₂H₅ H H C(CH₃)₃ CH₂CH₂CH₃ CH₂CH₂CH₃ HH C(CH₃)₃ CH₂(CH₂)₂CH₃ CH₂(CH₂)₂CH₃ H H C(CH₃)₃ CH₃ CH₃ CH₃ H C(CH₃)₃CH₃ CH₃ CH₃ CH₃ C(CH₃)₃ H H H H CH(CH₃)₂ H H H H CH(CH₃)CH₂CH₃ CH₃ H H HCH(CH₃)₂ CH₃ CH₃ H H CH(CH₃)₂ CH(CH₃)₂ CH(CH₃)₂ H H CH(CH₃)₂ CH(CH₃)₂CH(CH₃)₂ H H C(CH₃)₃ CH₃ CH₃ H H H CH₃ H H CH₃ H CH₃ H H H CH₃ H H CH₃CH₃ H CH₃ CH₃ H H CH₃ CH₃ CH₃ CH₃ H CH₃ CH₃ CH₃ CH₃ CH₃ CH₃ C₂H₅ C₂H₅ HH H C₂H₅ C₂H₅ H H C₂H₅ C₂H₅ C₂H₅ H H C(CH₃)₃ CH₂CH₂CH₃ CH₂CH₂CH₃ H HCH₂CH₂CH₃ CH₂(CH₂)₂CH₃ CH₂(CH₂)₂CH₃ H H CH₂(CH₂)₂CH₃ CH₂(CH₂)₃CH₃CH₂(CH₂)₃CH₃ H H CH₂(CH₂)₃CH₃ CH₂(CH₂)₄(CH₃ CH₂(CH₂)₄CH₃ H HCH₂(CH₂)₄CH₃ CH₂(CH₂)₅CH₃ CH₂(CH₂)₅CH₃ H H CH₂(CH₂)₅CH₃ CH₂(CH₂)₆CH₃CH₂(CH₂)₆CH₃ H H CH₂(CH₂)₆CH₃ H H H H F H H H H Cl H H H H Br H H H H IH H CH₃ H Cl H H CH₃ CH₃ Cl CH₃ H CH₃ CH₃ Cl CH₃ CH₃ CH₃ CH₃ Cl CH₃ CH₃CH₃ CH₃ Br CH₃ CH₃ CH₃ CH₃ F CH₃ CH₃ Cl H H CH₃ CH₃ Cl Cl H CH₃ CH₃ Cl HCH₃ CH₃ CH₃ Cl Cl CH₃ CH₃ CH₃ Cl Cl CH₂CH₃ CH₃ CH₃ Cl H CH(CH₃)₂ CH₃ CH₃Cl Cl CH(CH₃)₂ CH₃ CH₃ Cl H C(CH₃)₃ CH₃ CH₃ Cl Cl C(CH₃)₃ CH₃ CH₃ F HC(CH₃)₃ CH₃ CH₃ F F C(CH₃)₃ CH₂OCH₃ H H H H CH(CH₃)OCH₃ H H H HC(CH₃)₂OCH₃ H H H H CH₂CH₂OCH₃ H H H H CH₂OCH₂CH₃ H H H H CH₂OCH₂CH₂CH₃H H H H CH₂OCH(CH₃)₂ H H H H CH₂OCH₂(CH₂)₂CH₃ H H H H CH₂OC(CH₃)₃ H H HH CH₂OCH₂CH₂OCH₃ H H H H CH₂OCH₂CH₂OCH₂CH₃ H H H H CH₂OCH₂CH₂CH₂OCH₃ H HH H CH₂O(CH₂CH₂O)₂CH₃ H H H H CH₂OCH₃ CH₂OCH₃ H H H CH₂OCH₃ H CH₂OCH₃ HH CH₂OCH₃ H H CH₂OCH₃ H CH₂OCH₃ H H H CH₂OCH₃ CH₂OCH₃ CH₂OCH₃ CH₂OCH₃ HH CH₂OCH₃ CH₂OCH₃ H H CH₂OCH₃ CH(CH₃)OCH₃ CH(CH₃)OCH₃ H H CH(CH₃)OCH₃C(CH₃)₂OCH₃ C(CH₃)₂OCH₃ H H C(CH₃)₂OCH₃ CH₂OCH₂CH₃ CH₂OCH₂CH₃ H H HCH₂OCH₂CH₂CH₃ CH₂OCH₂CH₂CH₃ H H H CH₂OCH(CH₃)₂ CH₂OCH(CH₃)₂ H H HCH₂OCH₂(CH₂)₂CH₃ CH₂OCH₂(CH₂)₂CH₃ H H H CH₂OCH₂CH(CH₃)₂ CH₂OCH₂CH(CH₃)₂H H H CH₂OCH(CH₃)CH₂CH₃ CH₂OCH(CH₃)CH₂CH₃ H H H CH₂OC(CH₃)₃ CH₂OC(CH₃)₃H H H CH₂OCH₂C(CH₃)₃ CH₂OCH₂C(CH₃)₃ H H H CH₂OCH₃ CH₃ H H H CH₂OCH₃ HCH₃ H H CH₂OCH₃ H H CH₃ H CH₂OCH₃ H H H CH₃ CH₂OCH₃ CH₃ H H CH₃ CH₂OCH₃CH₃ H H CH(CH₃)₂ CH₂OCH₃ CH₃ H H C(CH₃)₃ CH₂OCH₃ CH₂OCH₃ H H CH₃ CH₂OCH₃CH₂OCH₃ H H CH₂CH₃ CH₂OCH₃ CH₂OCH₃ H H CH₂CH₂CH₃ CH₂OCH₃ CH₂OCH₃ H HCH(CH₃)₂ CH₂OCH₃ CH₂OCH₃ H H C(CH₃)₃ CH₂OCH₃ CH₂OCH₃ Cl H C(CH₃)₃CH₂OCH₃ CH₂OCH₃ Cl Cl C(CH₃)₃ CH₂OCH₃ CH₂OCH₃ F H C(CH₃)₃ CH₂OCH₃CH₂OCH₃ F F C(CH₃)₃ CH₂OCH₃ CH₂OCH₃ H H F CH₂OCH₃ CH₂OCH₃ H H ClCH₂OCH₂CH₃ CH₂OCH₂CH₃ H H C(CH₃)₃ CH₂OCH₂CH₂CH₃ CH₂OCH₂CH₂CH₃ H HC(CH₃)₃ CH₂OCH(CH₃)₂ CH₂OCH(CH₃)₂ H H C(CH₃)₃ CH₂OCH₂CH₂CH₂CH₃CH₂OCH₂CH₂CH₂CH₃ H H C(CH₃)₃ CH₂OCH₂CH(CH₃)₂ CH₂OCH₂CH(CH₃)₂ H H C(CH₃)₃CH₂OCH(CH₃)CH₂CH₃ CH₂OCH(CH₃)CH₂CH₃ H H C(CH₃)₃ CH₂OC(CH₃)₂ CH₂OC(CH₃)₂H H C(CH₃)₃ CH(CH₃)OCH₃ CH(CH₃)OCH₃ H H H C(CH₃)₂OCH₃ C(CH₃)₂OCH₃ H H HC(CH₃)₂OCH₃ C(CH₃)₂OCH₃ H H C(CH₃)₃ CH₂OCH₂CH₂OCH₃ CH₂OCH₂CH₂OCH₃ H HC(CH₃)₃ CH₂OCH₂CH₂CH₂OCH₃ CH₂OCH₂CH₂CH₂OCH₃ H H C(CH₃)₃CH₂O(CH₂CH₂O)₂CH₃ CH₂O(CH₂CH₂O)₂CH₃ H H C(CH₃)₃ CH₂CH₂OCH₃ CH₂CH₂OCH₃ HH C(CH₃)₃ CH₂CH₂OCH₂CH₃ CH₂CH₂OCH₂CH₃ H H C(CH₃)₃ CH₂CH₂OCH₂CH₂OCH₃CH₂CH₂OCH₂CH₂OCH₃ H H C(CH₃)₃

Embodiments of formula (I) can be compounds represented by formula (Ia):

in which

R^(1a) and R^(1b) are independently a hydrogen atom; a primary orsecondary alkyl group having from one to eight carbon atoms; or aprimary, secondary, or tertiary alkyl group having two to eight carbonatoms and at least one ether linkage; and

R^(2a′) and R^(2b′) are independently a hydrogen atom or a halogen atom;and

R³ is a hydrogen atom; a halogen atom; a primary, secondary, or tertiaryalkyl group having from one to eight atoms; or a primary, secondary, ortertiary alkyl group having two to eight carbon atoms and at least oneether linkage;

provided that, when R³ is a hydrogen atom, R^(1a) and R^(1b) areindependently a primary or secondary alkyl group having from one toeight carbon atoms or at least one of R^(1a) and R^(1b) is a primary,secondary, or tertiary alkyl group having two to eight carbon atoms andat least one ether linkage, and,

when R³ is a primary alkyl group having one to eight carbon atoms, atleast one of R^(1a) and R^(1b) is a primary or secondary alkyl grouphaving from one to eight carbon atoms, or a primary, secondary, ortertiary alkyl group having two to eight carbon atoms and at least oneether linkage.

Examples of the alkyl groups of R^(1a), R^(1b) and R³ are the same asabove. Examples of preferred halogen atoms of R³ are as previouslydescribed, and examples of preferred halogen atoms of R^(2a′) andR^(2b′) are the same as the halogen atoms of R³.

In preferred embodiments the alkyl groups of formula (Ia) have from oneto four carbon atoms, and the alkyl groups having at least one etherlinkage have from two to five carbon atoms. Preferred alkyl groups of R³are tertiary alkyl groups and the most preferred alkyl group of R³ istert-butyl group.

Table 1a provides illustrative combinations of R^(1a), R^(1b), R^(2a′),R^(2b′) and R³ for inclusion in formula (Ia).

TABLE 1a Illustrative Examples of Substituted Phenylsulfur TrifluorideCompounds of Formula (Ia) Showing R^(1a), R^(1b), R^(2a′), R^(2b′), andR³ Combinations Based On Substitutions Into Formula (Ia) R^(1a) R^(1b)R^(2a′) R^(2b′) R³ H H H H C(CH₃)₃ H H H H C(CH₃)₂C₂H₅ H H H HC(CH₃)₂(CH₂)₂CH₃ H H H H C(CH₃)₂(CH₂)₃CH₃ H H H H C(CH₃)₂(CH₂)₄CH₃ CH₃ HH H C(CH₃)₃ CH₃ CH₃ H H C(CH₃)₃ CH₃ CH₃ Cl H C(CH₃)₃ CH₃ CH₃ Cl ClC(CH₃)₃ CH₃ CH₃ F H C(CH₃)₃ CH₃ CH₃ F F C(CH₃)₃ H H H H CH(CH₃)₂ H H H HCH(CH₃)C₂H₅ CH₃ H H H CH(CH₃)₂ CH₃ CH₃ H H CH(CH₃)₂ CH(CH₃)₂ CH(CH₃)₂ HH CH(CH₃)₂ CH(CH₃)₂ CH(CH₃)₂ H H C(CH₃)₃ CH₃ CH₃ H H H CH₃ H H H CH₃ CH₃CH₃ H H CH₃ CH₃ CH₃ Cl H CH₃ CH₃ CH₃ Cl Cl CH₃ C₂H₅ C₂H₅ H H H C₂H₅ C₂H₅H H C₂H₅ C₂H₅ C₂H₅ H H C(CH₃)₃ CH₂CH₂CH₃ CH₂CH₂CH₃ H H CH₂CH₂CH₃CH₂(CH₂)₂CH₃ CH₂(CH₂)₂CH₃ H H CH₂(CH₂)₂CH₃ CH₂(CH₂)₃CH₃ CH₂(CH₂)₃CH₃ H HCH₂(CH₂)₃CH₃ CH₂(CH₂)₄CH₃ CH₂(CH₂)₄CH₃ H H CH₂(CH₂)₄CH₃ CH₂(CH₂)₅CH₃CH₂(CH₂)₅CH₃ H H CH₂(CH₂)₅CH₃ CH₂(CH₂)₆CH₃ CH₂(CH₂)₆CH₃ H H CH₂(CH₂)₆CH₃H H H H F H H H H Cl H H H H Br H H H H I CH₃ H H H Cl CH₃ CH₃ H H ClCH₃ CH₃ H H Br CH₃ CH₃ H H F CH₂OCH₃ H H H H CH₂OCH₂CH₂OCH₃ H H H HCH₂OCH₂CH₂CH₂OCH₃ H H H H CH₂OCH₂CH₂OCH₂CH₃ H H H H CH₂O(CH₂CH₂O)₂CH₃ HH H H H H H H CH₂OCH₃ CH₂OCH₃ CH₂OCH₃ H H H CH₂OCH₃ H H H CH₂OCH₃CH₂OCH₃ CH₂OCH₃ H H CH₂OCH₃ CH(CH₃)OCH₃ CH(CH₃)OCH₃ H H H CH(CH₃)OCH₃CH(CH₃)OCH₃ H H CH(CH₃)OCH₃ C(CH₃)₂OCH₃ C(CH₃)₂OCH₃ H H H C(CH₃)₂OCH₃C(CH₃)₂OCH₃ H H C(CH₃)₂OCH₃ CH₂OCH₂CH₂OCH₃ CH₂OCH₂CH₂OCH₃ H H H CH₂OCH₃CH₂OCH₃ H H CH₃ CH₂OCH₃ CH₂OCH₃ H H C(CH₃)₃ CH₂OCH₃ CH₂OCH₃ Cl H C(CH₃)₃CH₂OCH₃ CH₂OCH₃ Cl Cl C(CH₃)₃ CH₂OCH₃ CH₂OCH₃ F H C(CH₃)₃ CH₂OCH₃CH₂OCH₃ F F C(CH₃)₃ CH₂OCH₂CH₃ CH₂OCH₂CH₃ H H C(CH₃)₃ CH₂OCH₂CH₂CH₃CH₂OCH₂CH₂CH₃ H H C(CH₃)₃ CH₂OCH(CH₃)₂ CH₂OCH(CH₃)₂ H H C(CH₃)₃CH₂OCH₂CH₂CH₂CH₃ CH₂OCH₂CH₂CH₂CH₃ H H C(CH₃)₃ CH₂OCH₂CH₂(CH₃)₂CH₂OCH₂CH₂(CH₃)₂ H H C(CH₃)₃ CH₂OCH(CH₃)CH₂CH₃ CH₂OCH(CH₃)CH₂CH₃ H HC(CH₃)₃ CH₂OC(CH₃)₃ CH₂OC(CH₃)₃ H H C(CH₃)₃ CH(CH₃)OCH₃ CH(CH₃)OCH₃ H HC(CH₃)₃ C(CH₃)₂OCH₃ C(CH₃)₂OCH₃ H H C(CH₃)₃ CH₂CH₂OCH₃ CH₂CH₂OCH₃ H HC(CH₃)₃ CH₂OCH₂CH₂OCH₃ CH₂OCH₂CH₂OCH₃ H H C(CH₃)₃ CH₂OCH₃ CH₂OCH₃ H H ClCH₂OCH₃ CH₂OCH₃ H H F CH₂OCH₂CH₂OCH₃ H H H H CH₂OCH₃ CH₃ H H CH₃ CH₂OCH₃CH₃ H H C(CH₃)₃

Preferred embodiments of formula (Ia) are compounds having a formula(II):

in which

R^(1a′) and R^(1b′) are independently a hydrogen atom or a primary orsecondary alkyl group having from one to eight carbon atoms; and

R^(3′) is a hydrogen atom, a halogen atom, or a primary, secondary, ortertiary alkyl group having from one to eight carbon atoms, providedthat, when R^(3′) is a hydrogen atom, R^(1a′) and R^(1b′) areindependently primary or secondary alkyl groups having from one to eightcarbon atoms and, when R^(3′) is a primary alkyl group having from oneto eight carbon atoms, at least one of R^(1a′) and R^(1b′) is a primaryor secondary alkyl group having from one to eight carbon atoms. Examplesof the primary or secondary alkyl groups of R^(1a′) and R^(1b′) havingone to eight carbon atoms are the same as examples of the primary orsecondary alkyl groups of R^(1a) and R^(1b) having one to eight carbonatoms, which are described previously. Examples of the primary,secondary, or tertiary alkyl groups of R^(3′) having from one to eightcarbon atoms are the same as examples of the primary, secondary, ortertiary alkyl groups of R³ having from one to eight carbon atoms, whichare described previously. Examples of the halogen atoms of R^(3′) arethe same as examples of the halogen atoms of R³, which are describedpreviously. In preferred embodiments the alkyl groups of formula (II)have from one to four carbon atoms. More preferred alkyl groups ofR^(3′) are tertiary alkyl groups and the most preferred alkyl group ofR^(3′) is tert-butyl group.

Table 2 provides illustrative combinations of R^(1a′), R^(1b′) andR^(3′) for inclusion in formula (II).

TABLE 2 Illustrative Examples of Substituted Phenylsulfur TrifluorideCompounds of Formula (II) Showing R^(1a′), R^(1b′), and R^(3′)Combinations Based On Substitutions Into Formula (II) R^(1a′) R^(1b′)R^(3′) H H C(CH₃)₃ H H C(CH₃)₂C₂H₅ H H C(CH₃)₂(CH₂)₂CH₃ H HC(CH₃)₂(CH₂)₃CH₃ H H C(CH₃)₂(CH₂)₄CH₃ CH₃ H C(CH₃)₃ CH₃ CH₃ C(CH₃)₃ H HCH(CH₃)₂ H H CH(CH₃)C₂H₅ CH₃ H CH(CH₃)₂ CH₃ CH₃ CH(CH₃)₂ CH(CH₃)₂CH(CH₃)₂ CH(CH₃)₂ CH(CH₃)₂ CH(CH₃)₂ C(CH₃)₃ CH₃ CH₃ H CH₃ H CH₃ CH₃ CH₃CH₃ C₂H₅ C₂H₅ H C₂H₅ C₂H₅ C₂H₅ C₂H₅ C₂H₅ C(CH₃)₃ CH₂CH₂CH₃ CH₂CH₂CH₃CH₂CH₂CH₃ CH₂(CH₂)₂CH₃ CH₂(CH₂)₂CH₃ CH₂(CH₂)₂CH₃ CH₂(CH₂)₃CH₃CH₂(CH₂)₃CH₃ CH₂(CH₂)₃CH₃ CH₂(CH₂)₄CH₃ CH₂(CH₂)₄CH₃ CH₂(CH₂)₄CH₃CH₂(CH₂)₅CH₃ CH₂(CH₂)₅CH₃ CH₂(CH₂)₅CH₃ CH₂(CH₂)₆CH₃ CH₂(CH₂)₆CH₃CH₂(CH₂)₆CH₃ H H F H H Cl H H Br H H I CH₃ H Cl CH₃ CH₃ Cl CH₃ CH₃ BrCH₃ CH₃ F

Another preferred embodiment of formula (Ia) is compounds having aformula (Ib):

in which

R^(3′) is a hydrogen atom, a halogen atom, or a primary, secondary, ortertiary alkyl group having from one to eight carbon atoms;

R⁴ is a primary, secondary, or tertiary alkyl group; and

R⁵ and R⁶ are independently an alkylene group; the total carbon numberof R⁴, R⁵, and R⁶ is eight or less, and m is 0 or 1.

In preferred embodiments the alkyl groups of formula (Ib) have fourcarbons or less; the alkylene groups of formula (Ib) have four carbonsor less; and m is 0. Preferred R^(3′) is a hydrogen atom or a tertiaryalkyl group, more preferred R^(3′) is a tertiary alkyl group, and mostpreferred R^(3′) is tert-butyl group.

Examples of alkyl groups of R^(3′) having a primary, secondary, ortertiary alkyl group having from one to eight atoms are the same asdescribed above. Examples of the halogen atoms of R^(3′) are the same asdescribed above.

The primary, secondary, or tertiary alkyl groups of R⁴ include; primaryalkyl groups such as CH₃, CH₂CH₃, CH₂(CH₂)_(n)CH₃ (n=1-5), CH₂CH(CH₃)₂,and CH₂C(CH₃)₃, secondary alkyl groups such as CH(CH₃)₂, CH(CH₃)CH₂CH₃,and CH(CH₃)CH₂(CH₂)_(n)CH₃ (n=1-3), and tertiary alkyl groups such asC(CH₃)₃, C(CH₃)₂CH₂CH₃, and C(CH₃)₂CH₂(CH₂)_(n)CH₃ (n=1, 2). From theviewpoint of stability for a compound having formula (Ib), R⁴ ispreferably a primary or secondary alkyl group. Preferred primary alkylgroups of R⁴ include: CH₃, CH₂CH₃, CH₂(CH₂)_(n)CH₃ (n=1, 2),CH₂CH(CH₃)₂, and CH₂C(CH₃)₃ and preferred secondary alkyl groups of R⁴include: CH(CH₃)₂ and CH(CH₃)CH₂CH₃. One preferred primary alkyl groupof R⁴ is CH₃ and most preferred secondary alkyl group of R⁴ includesCH(CH₃)₂.

The alkylene groups of R⁵ and R⁶ include; CH₂, CH₂CH₂, CH₂(CH₂)_(n)CH₂(n=1, 2), CH(CH₃), CH(CH₂CH₃), CH₂CH(CH₃), CH(CH₃)CH₂, C(CH₃)₂,CH₂C(CH₃)₂, C(CH₃)₂CH₂ and CH[CH(CH₃)₂]. Preferred allylene groups of R⁵are CH₂, CH₂CH₂, and CH₂CH₂CH₂, and most preferred alkylene groups of R⁵are CH₂. Preferred alkylene groups of R⁶ are CH₂CH₂, CH₂CH(CH₃),CH(CH₃)CH₂ and CH₂CH₂CH₂, and most preferred alkylene group of R⁶ isCH₂CH₂.

Table 2a provides illustrative combinations of R^(3′), R⁴, R⁵, R⁶, and mfor inclusion in formula (Ib).

TABLE 2a Illustrative Examples of Substituted Phenylsulfur TrifluorideCompounds of Formula (Ib) Showing R^(3′), R⁴, R⁵, R⁶ and m CombinationsBased On Substitutions Into Formula (Ib) R^(3′) R⁵(OR⁶)_(m)O(m = 0 or 1)R⁴ H CH₂O CH₃ H CH₂O C₂H₅ H CH₂O CH₂CH₂CH₃ H CH₂O CH(CH₃)₂ H CH₂OCH₂(CH₂)₂CH₃ H CH₂O CH(CH₃)CH₂CH₃ H CH₂O CH₂CH(CH₃)₂ H CH₂O C(CH₃)₃ HCH₂O CH₂C(CH₃)₃ H CH(CH₃)O CH₃ H C(CH₃)₂O CH₃ H CH(CH₂CH₃)O CH₃ HCH[CH(CH₃)₂]O CH₃ H CH₂CH₂O CH₃ H CH₂CH(CH₃)O CH₃ H CH(CH₃)CH₂O CH₃ HCH₂C(CH₃)₂O CH₃ H C(CH₃)₂CH₂O CH₃ H CH₂OCH₂CH₂O CH₃ CH₃ CH₂O CH₃ C₂H₅CH₂O CH₃ CH₂CH₂CH₃ CH₂O CH₃ CH(CH₃)₂ CH₂O CH₃ CH₂(CH₂)₂CH₃ CH₂O CH₃CH(CH₃)CH₂CH₃ CH₂O CH₃ CH₂CH(CH₃)CH₃ CH₂O CH₃ C(CH₃)₃ CH₂O CH₃ C(CH₃)₃CH₂O C₂H₅ C(CH₃)₃ CH₂O CH₂CH₂CH₃ C(CH₃)₃ CH₂O CH(CH₃)₂ C(CH₃)₃ CH₂OCH₂CH₂CH₂CH₃ C(CH₃)₃ CH₂O CH₂CH(CH₃)₂ C(CH₃)₃ CH₂O CH(CH₃)CH₂CH₃ C(CH₃)₃CH₂O C(CH₃)₃ C(CH₃)₃ CH(CH₃)O CH₃ C(CH₃)₃ CH[CH(CH₃)₂]O CH₃ C(CH₃)₃C(CH₃)₂O CH₃ C(CH₃)₃ CH₂CH₂O CH₃ C(CH₃)₃ CH₂OCH₂CH₂O CH₃ C(CH₃)₃CH₂CH₂OCH₂CH₂O CH₃ F CH₂O CH₃ Cl CH₂O CH₃ Br CH₂O CH₃ I CH₂O CH₃

The fluorinating agents of the present invention are typically providedin substantially pure form, for example at least 50% pure, moretypically 60% pure, advantageously at least 75% pure and preferably atleast 85% or 90% pure. All percentages are calculated on a weight/weightbasis.

The fluorinating agents of the present invention may also be combinationof any two or more fluorinating agents described herein (see Examples inTable 5).

It will be understood by one of skill in the relevant art that certaincompounds of the invention may comprise one or more chiral centers sothat the compounds may exist as stereoisomers, includingdiastereoisomers and enantiomers. It is envisioned that all suchcompounds be within the scope of the present invention, including allsuch stereoisomers, and mixtures thereof, including racemates.

Fluorinating agents of the invention may be prepared according to themethods as described in the Examples below, see particularly Examples 2,3, 3a-c, 4-15, and 15a-g. In addition, methods reported in theliterature may be modified to produce various agents illustrated inTables 1, 1a, 2 and 2a [see J. Am. Chem. Soc., Vol. 84, pp 3058-3063(1962); Synthetic Communications, Vol. 33, No. 14, pp 2505-2509 (2003)].

Typically, the starting materials for synthesis of the substitutedphenylsulfur trifluorides of the invention are the correspondingsubstituted biphenyl disulfides, which are either commerciallyavailable, prepared by oxidation of the corresponding substitutedthiophenols, prepared from the corresponding substituted benzenesulfonylhalides (see for example the methods as shown in Examples 1, 1a, 1c, and1d), or are prepared from the corresponding substituted phenyl halides(see for example the methods as shown in Examples 1b, 1e, 1f, 1g, 1 h,and 1j).

The present invention providesbis(2,6-dimethyl-3-chloro-4-tert-butylphenyl) disulfide andbis(2,6-dimethyl-3,5-dichloro-4-tert-butylphenyl)disulfide which areuseful intermediates for synthesis of the novel substituted phenylsulfurtrifluorides of the present invention.

The present invention also provides the compound of formula (Ic);

in which:

-   -   R⁷ is a primary, secondary, or tertiary alkyl group having from        one to four carbon atoms, and R⁸ is a hydrogen atom or a        primary, secondary, or tertiary alkyl group having from one to        four carbon atoms.

The compounds of formula (Ic) are useful intermediates in the synthesisof the novel substituted phenylsulfur trifluorides of the presentinvention.

Some embodiments of the invention are those compounds of formula (Ic)where primary, secondary, or tertiary alkyl groups of R⁷ having from oneto four carbon atoms include: primary alkyl groups such as CH₃, CH₂CH₃,CH₂(CH₂)_(n)CH₃ (n=1, 2), and CH₂CH(CH₃)₂, secondary alkyl groups suchas CH(CH₃)₂ and CH(CH₃)CH₂CH₃, and tertiary alkyl groups such asC(CH₃)₃. More preferred alkyl groups of R⁷ include: CH₃, CH₂CH₃,CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, and C(CH₃)₃ and the most preferredalkyl groups of R⁷ include CH₃, CH₂CH₃, CH(CH₃)₂, CH₂CH(CH₃)₂, andC(CH₃)₃.

Other embodiments of the invention are those compounds of formula (Ic)where primary, secondary, or tertiary alkyl groups having from one tofour carbon atoms of R⁸ include: CH₃, CH₂CH₃, CH₂(CH₂)_(n)CH₃ (n=1, 2),CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)₂, and C(CH₃)₃. More preferred alkylgroups having from one to four carbon atoms of R⁸ include: CH₃, CH₂CH₃,CH(CH₃)₂, C(CH₃)₃, and highly preferred alkyl group of R⁸ includesC(CH₃)₃.

While not being tied to any particular mechanism, the unexpectedfunctional activities of the novel substituted phenylsulfur trifluoridesof the present invention are due, at least in part, to their relativelyhigh stability. The high stability of these substituted phenylsulfurtrifluorides is due at least in part, to high decomposition temperaturesand low exothermal heat (−ΔH) (see Examples 16, 16a,b, 17-25, and 25a,b)as compared to more conventional fluorinating agents. These values canbe compared to the values for other conventional fluorinating agents(see Table 4), where DAST and Deoxo-Fluor® have a decompositiontemperature of about 140° C. and exothermic heat values of 1100-1700 J/gas compared to compounds of the invention where decompositiontemperatures of about 175-320° C. and exothermic heat of 350-700 J/g aretypical (see Table 4).

The novel phenylsulfur trifluorides of the present invention also havehigh stability in water as compared to conventional fluorinating agents,such as DAST, and Deoxo-Fluor®, (which are known to be dangerous becauseof vigorous reaction when contacted with water (see Table 6)). Note thatphenylsufur trifluoride (PhSF₃) and p-methylphenylsulfur trifluoride(p-CH₃C₆H₄SF₃) are similar to DAST and Deoxy-Fluor. Unexpectedly andsurprisingly, the substituted phenylsulfur trifluorides of theinvention, such as 2,6-dimethyl-4-tert-butylphenylsulfur trifluoride,2,6-dimethyl-3,5-dichloro-4-tert-butylphenylsulfur trifluoride,2,6-bis(methoxymethyl)phenylsulfur trifluoride,2,6-bis(methoxymethyl)-4-tert-butylphenylsulfur trifluoride,2,6-bis(ethoxymethyl)-4-tert-butylphenylsulfur trifluoride,2,6-bis(isopropoxymethyl)-4-tert-butylphenylsulfur trifluoride,2,6-bis(isobutoxymethyl)-4-tert-butylphenylsulfur trifluoride, and amixture of 2,6-dimethyl-4-tert-butylphenylsulfur trifluoride and2,6-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride, have littleor no reaction when contacted with water. Alkyl groups such astert-butyl group and alkyl groups having at least one ether linkagebrought about unexpected and surprising high stability against water andmoisture. Therefore, the phenylsulfur trifluorides of the presentinvention have high stability, storage stability, safety, safe handling,and safe disposability as compared to many conventional agents.

EXAMPLES

The following examples are provided for illustrative purposes only andare not intended to limit the scope of the invention. Table 3 providesstructure names and formulas for reference when reviewing the followingexamples:

TABLE 3 Substituted Phenylsulfur Trifluorides (Formulas IV, IVa, b,V-XIX) and Starting Materials (Formulas III,IIIa-h): Formula Number NameStructure III Bis(2,6-dimethyl-4-tert- butylphenyl) disulfide

IIIa Bis(2,6-dimethyl-3-chloro-4- tert-butylphenyl) disulfide

IIIb Bis(2,6-dimethyl-3,5-dichloro-4- tert-butylphenyl) disulfide

IIIc Bis[2,6- bis(methoxymethyl)phenyl] disulfide

IIId Bis[2,6-bis(methoxymethyl)-4- tert-butylphenyl] disulfide

IIIe Bis[2,6-bis(ethoxymethyl)-4- tert-butylphenyl] disulfide

IIIf Bis[2,6-bis(isopropoxymethyl)- 4-tert-butylphenyl] disulfide

IIIg Bis[2,6-bis(isobutoxymethyl)-4- tert-butylphenyl] disulfide

IIIh Bis[2,6-bis(tert-butoxymethyl)- 4-tert-butylphenyl] disulfide

IV 2,6-Dimethyl-4-tert- butylphenylsulfur trifluoride

IVa 2,6-Dimethyl-3-chloro-4-tert- butylphenylsulfur trifluoride

IVb 2,6-Dimethyl-3,5-dichloro-4- tert-butylphenylsulfur trifluoride

V 4-tert-Butylphenylsulfur trifluoride

VI 2,4,6-Trimethylphenylsulfur trifluoride

VII 2,4-Dimethylphenylsulfur trifluoride

VIII 2,5-Dimethylphenylsulfur trifluoride

IX 2,6-Dunethylphenylsulfur trifluoride

X 4-Fluorophenylsulfur trifluoride

XI 4-Chlorophenylsulfur trifluoride

XII 3-Methyl-4-chlorophenylsulfur trifluoride

XIII 2,4,6-Tri(isopropyl)phenylsulfur trifluoride

XIV 2,6-Bis(methoxymethyl)phenyl sulfur trifluoride

XV 2,6-Bis(methoxymethyl)-4-tert- butylphenylsulfur trifluoride

XVI 2,6-Bis(ethoxymethyl)-4-tert- butylphenylsulfur trifluoride

XVII 2,6-Bis(isopropoxymethyl)-4- tert-butylphenylsulfur trifluoride

XVIII 2,6-Bis(isobutoxymethyl)-4-tert- butylphenylsulfur trifluoride

XIX 2,6-Bis(tert-butoxymethyl)-4- tert-butylphenylsulfur trifluoride

Example 1 Preparation of bis(2,6-dimethyl-4-tert-butylphenyl)disulfide

The following reaction scheme is provided as illustrative:

A two liter, three-neck flask, was obtained. A condenser with a dryingtube, a thermometer, and a dropping funnel were each attached to theflask. Zinc dust (<10 micron, 43.6 g, 0.667 mol) and anhydroustetrahydrofuran (400 mL) were added to the flask. The mixture wasstirred and cooled on an ice-water bath and 58.6 ml (0.534 mmol) oftitanium tetrachloride added drop wise (˜45 min). During the entireaddition of titanium tetrachloride, the temperature of the mixture wasmaintained below 25° C. Once the addition was complete, a solution of2,6-dimethyl-4-tert-butylbenzenesulfonyl chloride (69.48 g, 0.267 mol)in 200 mL of anhydrous tetrahydrofuran was added drop wise (˜60 min).During the entire addition of the material, the temperature of themixture was maintained below 20° C. At the conclusion of the2,6-dimethyl-4-tert-butylbenzenesulfonyl chloride addition, theice-water bath was removed, the mixture was allowed to stir anadditional 30 min. The mixture was then heated on an oil bath at 60° C.for 4 hours. The mixture was then cooled to room temperature and 800 mLof 1N hydrochloric acid and 300 mL of ice water added. The resultantpale yellow precipitates were collected by filtration and washed withwater (300 mL×3). The precipitate was then dried under vacuum and theprecipitates recrystallized from hexanes, giving 33.1 gbis(2,6-dimethyl-4-tert-butylphenyl) disulfide (see Formula III, Table3). The yield of the reaction was 70% and the material had the followingspectral data: ¹H NMR (CDCl₃) δ 7.04 (s, 4H, aromatic protons (Ar—H)),2.23 (s, 12H, CH₃), 1.30 (s, 18H, C(CH₃)₃).

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 1a Alternative Preparation ofbis(2,6-dimethyl-4-tert-butylphenyl) disulfide

A 5 liter, 3 neck, jacketed round bottom flask was set-up withmechanical stirrer, internal thermometer, and reflux condenser with agas exit through a plastic tube into an acid trap. The flask was chargedwith 885.8 g (3.40 mol) of 2,6-dimethyl-4-tert-butylbenzenesulfonylchloride, 388 g (4.12 mol) of phenol, and 1000 mL of glacial aceticacid. The reaction was heated to 35-40° C. with stirring until allreactants were dissolved. In the solution, 1600 mL of 33 wt % hydrogenbromide/acetic acid solution was added, essentially all at once, butslowly and carefully. The reaction appeared to begin at once withdarkening of the solution and a significant initial release of acid gas.With the jacket held at 35° C., a strong but steady exotherm raised theinternal temperature to a maximum of 47° C. over 20 min. When thetemperature began to subside, heating was applied and the jacket wasraised to 60° C., and held for approximately 6 hours total. The reactionwas then set-up for simple vacuum distillation to remove as much acidsolvents as possible. A total of 2350 mL was removed, leaving a thick,dark slurry in the flask. Water (1000-1500 mL) was added to the reactionmass, followed by sodium hydroxide to make the solution alkaline with apH of approximately 10 to remove acetic acid and other products,brominated phenols such as bromophenols and 2,4-dibromophenol. The darkbiphase slurry was then extracted with 2:1 ether/pentane. The organiclayer was separated and concentrated down on a rotary evaporator toyield dark slush which solidified upon cooling. The solid wasrecrystallized from a mixture of isopropanol (650 mL) and water (35 mL)to give 512.1 g (78% yield) ofbis(2,6-dimethyl-4-tert-butylphenyl)disulfide (formula III, Table 3),shown to be clean by TLC and NMR. ¹H NMR (CDCl₃) δ 7.02 (s, 4H, Ar—H),2.21 (s, 12H, CH₃), 1.29 (s, 18H, C(CH₃)₃).

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 1b Preparation ofbis(2,6-dimethyl-3-chloro-4-tert-butylphenyl)disulfide

In a three neck dry flask equipped with a water condenser, 33 g (0.12mol) of 2,6-dimethyl-3-chloro-4-tert-butylphenyl bromide, and 2.8 g(0.12 mol) of magnesium were mixed in anhydrous THF (200 ml). Acatalytic amount of iodine was added and the mixture was heated to 80°C. The mixture was refluxed 2 h and cooled on an ice bath. Sulfur powder3.8 g, (0.12 mole) was added portion wise. The mixture was heated to 80°C. for 2 h and cooled on an ice bath. A solution of potassiumhexacyanoferrate, 239.48 g (0.12 mol) in water (300 mL) was added. Aftermixing well, product was extracted with ether (200 mL). The etherextract was dried over anhydrous magnesium sulfate and filtered. Removalof solvent at reduced pressure gave a viscous solid which wascrystallized from ethanol to give 13.6 g (50%) ofbis(2,6-dimethyl-3-chloro-4-tert-butylphenyl)disulfide (formula IIIa,Table 3): Mp 128-129° C.; ¹H NMR (CDCl₃) δ 1.49 (s, 18H, C(CH₃)₃), 2.245(s, 6H, CH₃), 2.252 (s, 6H, CH₃) 7.14 (s, 2H, Ar—H).

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 1c Preparation of bis(2,6-dimethyl-3-chloro-4-tert-butylphenyl)disulfide

In a flask, 15.6 g (53 mmol) of2,6-dimethyl-3-chloro-4-tert-butylbenzenesulfonyl chloride, 6.0 g (64mmol) of phenol and 20 mL of glacial acetic acid were placed. The flaskwas heated on a bath of 35° C. Approximately 30 mL (165 mmol of HBr) of33 wt % hydrogen bromide/acetic acid solution was added to the flask.The reaction mixture was slowly heated at 60° C. A strong acidic gasevolved from the reaction mixture. The reaction mixture was stirred at60° C. for 4.5 hours and cooled to room temperature. Into the reactionmixture, 250 mL of water was added, and the reaction mixture wasfiltered to give precipitates. The precipitates were washed with water.The obtained precipitates were added to 100 mL of isopropanol and themixture stirred, the precipitates were collected by filtration to give10.3 g (86%) ofbis(2,6-dimethyl-3,5-dichloro-4-tert-butylphenyl)disulfide (formulaIIIa, Table 3). The spectral data were in good agreement with the datain Example 1b.

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 1d Preparation ofbis(2,6-dimethyl-3,5-dichloro-4-tert-butylphenyl) disulfide

Using a synthesis procedure similar to the one described in Example 1c,bis(2,6-dimethyl-3,5-dichloro-4-tert-butylphenyl)disulfide was prepared.However, unlike in Example 1c,2,6-dimethyl-3,5-dichloro-4-tert-butylbenzenesulfonyl chloride was usedinstead of 2,6-dimethyl-3-chloro-4-tert-butylbenzenesulfonyl chloride.

The above described synthesis procedure produced2,6-dimethyl-3,5-dichloro-4-tert-butylbenzenesulfonyl chloride (seeFormula IIIb, Table 3). A yield of 73% was obtained. The physical andspectral data of the material are as follows: Mp 147.5-148.5° C.(recrystallized from CH₂Cl₂); ¹H NMR (CDCl₃) δ 1.72 (s, 18H, C(CH₃)₃),2.31 (s, 6H, CH₃). Elemental analysis: Calculated for C₂₄H₃₀O₄S₂: C,54.97%; H, 5.77%. Found: C, 55.02%; H, 5.81%.

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 1e Preparation of bis[2,6-bis(methoxymethyl)phenyl]disulfide

In a three neck dry flask equipped with a water condenser, 15 g (0.061mol) of 1-bromo-2,6-bis(methoxymethyl)benzene and 1.7 g (0.07 mol) ofmagnesium were mixed in anhydrous THF (200 mL). A catalytic amount ofiodine was added and the mixture was heated to reflux. After refluxingfor 2 hours the reaction was cooled on an ice bath and sulfur was addedpinch wise. The mixture was refluxed for 2 additional hours and cooledon an ice bath. A solution of potassium hexacyanoferrate, 2.0 g (0.07mol) in water (200 mL) was added. After mixing well, product wasextracted with ether (200 mL). The ether extract was dried overanhydrous magnesium sulfate and filtered. Removal of solvent at reducedpressure gave viscous solid which was crystallized from ethanol to give8.3 g (65%) of bis[2,6-bis(methoxymethyl)phenyl]disulfide (formula IIId,Table 3): Mp 89-90° C.; ¹H-NMR (CDCl₃) δ 3.27 (s, 6H, OCH₃), 4.36 (br.s,4H, CH₂), 7.39 (s, 3H, Ar—H). Elemental analysis: Calculated forC₂₀H₂₆O₄S₂: C, 60.88%; H, 6.64%. Found: C, 60.56%; H, 6.64%.

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 1f Preparation ofbis[2,6-di(methoxymethyl)-4-tert-butylphenyl]disulfide

Using a synthesis procedure similar to the one described in Example 1e,bis[2,6-bis(methoxymethyl)-4-tert-butylphenyl]disulfide was prepared.However, unlike in Example 1e,1-bromo-2,6-bis(methoxymethyl)-4-tert-butylbenzene was used instead of1-bromo-2,6-bis(methoxymethyl)benzene.

The above described synthesis procedure producedbis[2,6-bis(methoxymethyl)-4-tert-butylphenyl]disulfide (see FormulaIIId, Table 3). A yield of 65% was obtained. The physical and spectraldata of the material are as follows: Mp 94-95° C. (recrystallized fromethanol); ¹H-NMR (CDCl₃) δ 1.32 (s, 9H, C(CH₃)₃), 3.25 (s, 6H, OCH₃),4.37 (br.s, 4H, CH₂), 7.41 (s, 2H, Ar—H); ¹³C-NMR (CDCl₃) δ 31.3, 35.1,58.4, 72.5, 124.0, 128.6, 142.4, 153.7.

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 1g Preparation ofbis[2,6-bis(ethoxymethyl)-4-tert-butylphenyl]disulfide

Using a synthesis procedure similar to the one described in Example 1e,bis[2,6-bis(ethoxymethyl)-4-tert-butylphenyl]disulfide was prepared.However, unlike in Example 1e,1-bromo-2,6-bis(ethoxymethyl)-4-tert-butylbenzene was used instead of1-bromo-2,6-bis(methoxymethyl)benzene.

The above described synthesis procedure producedbis[2,6-bis(ethoxymethyl)-4-tert-butylphenyl]disulfide (see FormulaIIIe, Table 3). A yield of 66% was obtained. The physical and spectraldata of the material are as follows: Mp 62-63° C. (recrystallized frommethanol); ¹H-NMR (CDCl₃) δ 1.18 (t, 12H, CH₂CH₃), 1.31 (s, 9H,C(CH₃)₃), 3.38 (q, 8H, OCH₂), 4.40 (br.s, 8H, CH₂), 7.42 (s, 2H, Ar—H);¹³C, NMR (CDCl₃) δ 15.34, 31.31, 35.04, 66.05, 70.52, 124.03, 128.93,142.78, 153.57. Elemental analysis: Calcd for C₃₂H₅₀O₄S₂: C, 68.28%; H,8.95%. Found: C, 68.30%; H, 8.83%.

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 1h Preparation ofbis[2,6-bis(isopropoxymethyl)-4-tert-butylphenyl]disulfide

Using a synthesis procedure similar to the one described in Example 1e,bis[2,6-bis(isopropoxymethyl)-4-tert-butylphenyl]disulfide was prepared.However, unlike in Example 1e,1-bromo-2,6-bis(isopropoxymethyl)-4-tert-butylbenzene was used insteadof 1-bromo-2,6-bis(methoxymethyl)benzene and the product (IIIf) waspurified by column-chromatography using a 3:97 mixture of ethyl acetateand hexane as an eluent.

The above described synthesis procedure producedbis[2,6-bis(isopropoxymethyl)-4-tert-butylphenyl]disulfide (see FormulaIIIf, Table 3). A yield of 50% was obtained. The spectral data of thematerial are as follows: ¹H NMR (CDCl₃) δ 1.12 (d, J=6 Hz, 24H, CH₃),1.31 (s, 18H, C(CH₃)₃), 3.48 (septet, J=6.0 Hz, 4H, CH), 4.39 (br.s, 8H,CH₂), 7.45 (s, 4H); ¹³C NMR (CDCl₃) δ 22.28, 31.30, 35.05, 68.22, 71.57,124.30, 129.16, 143.14, 153.38.

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 1i Preparation ofbis[2,6-bis(isobutoxymethyl)-4-tert-butylphenyl]disulfide

Using a synthesis procedure similar to the one described in Example 1e,bis[2,6-bis(isobutoxymethyl)-4-tert-butylphenyl]disulfide was prepared.However, unlike in Example 1e,4-tert-butyl-2,6-bis(isobutoxymethyl)-1-bromobenzene was used instead of1-bromo-2,6-bis(methoxymethyl)benzene.

The above described synthesis procedure producedbis[2,6-bis(isobutoxymethyl)-4-tert-butylphenyl]disulfide (see FormulaIIIg, Table 3). A yield of about 60% was obtained. The product waspurified by thin-layered chromatography using a 3:97 (v/v) mixture ofethyl acetate and hexane as an eluent. The spectral data of the materialare as follows: ¹H NMR (CDCl₃) δ 0.91 (d, 24H, J=6 Hz, CH₃), 1.32 (s,18H, C(CH₃)₃), 1.90 (m, 4H, CH(CH₃)₂), 4.40 (br.s, 8H, CH₂), 7.45 (s,4H, Ar—H); ¹³C NMR (CDCl₃) δ 19.60, 28.62, 31.32, 35.06, 76.69, 77.64,123.78, 128.70, 142.86, 153.50.

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 1j Preparation ofbis[2,6-bis(tert-butoxymethyl)-4-tert-butylphenyl]disulfide

Using a synthesis procedure similar to the one described in Example 1e,bis[2,6-bis(tert-butoxymethyl)-4-tert-butylphenyl]disulfide wasprepared. However, unlike in Example 1e,1-bromo-2,6-bis(tert-butoxymethyl)-4-tert-butylbenzene was used insteadof 1-bromo-2,6-bis(methoxymethyl)benzene.

The above described synthesis procedure producedbis[2,6-bis(tert-butoxymethyl)-4-tert-butylphenyl]disulfide (see FormulaIIIh, Table 3). A yield of 80% was obtained. The physical and spectraldata of the material are as follows: Mp 120-121° C. (recrystallized frommethanol); ¹H NMR (CDCl₃) δ 1.15 (s, 36H), 1.31 (s, 18H), 4.38 (br.s,8H), 7.47 (s, 4H); ¹³C NMR (CDCl₃) δ 27.82, 31.34, 35.07, 62.28, 73.53,124.10, 128.32, 143.84. Elemental analysis: Calcd for C₄₀H₆₆O₄S₂: C,71.17%; H, 9.85%. Found: C, 71.25%; H, 9.84%.

The present example illustrates the utility of the present invention forsynthesizing intermediates for producing fluorinating agents that can beused to produce fluorine-containing compounds.

Example 2 Synthesis Embodiment of 2,6-dimethyl-4-tert-butylphenylsulfurtrifluoride, a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

A 100 ml fluoropolymer (PFA)-round flask equipped with a magneticstirrer, a thermometer and a solid addition funnel connected to a dryingtube, was flushed with dry nitrogen and charged with 16.08 grams (g)(111 mmol) of silver difluoride and 20 ml of anhydrous1,1,2-trichlorotrifluoroethane.Bis(2,6-dimethyl-4-tert-butylphenyl)disulfide (6.03 g, 16.3 mmol),charged in the solid addition funnel, was added to the stirred slurry insmall portions to maintain the temperature of reaction mixture between35° and 40° C. The addition of disulfide required approximately twentyminutes.

The reaction mixture was stirred for an additional thirty minutes atroom temperature, and then heated to reflux for about five minutes. Thereaction mixture was filtered under a blanket of dry nitrogen. After theevaporation of the solvent, the residue was distilled at reducedpressure to give 2,6-dimethyl-4-tert-butylphenylsulfur trifluoride shownas formula (IV), Table 4 (bp 92-93° C./0.5 mmHg, mp 59.1° C. (by DSC)).The compound was a white solid, yield of 5.20 g (64%).

The spectral data of the material is as follows: ¹⁹F NMR (THF-d₈) δ53.90 (d, J=60.7 Hz, 2F), −57.03 (t, J=60.7 Hz, 1F); ¹H NMR (CD₃CN) δ7.25 (s, 2H), 2.60 (s, 6H), 1.30 (s, 9H); ¹³C NMR (CD₃CN) δ 155.37 (s),141.61 (s), 133.74 (s), 127.56 (s), 34.45 (s), 30.25 (s), 19.09 (s); MS(EI) m/z 149.0 (M⁺+1-2F, 100.0), 250.1 (M⁺, 1.8); HRMS (EI) for C₉H₁₁F₃S(M⁺): found 250.101491. calcd 250.100307.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 3 Synthesis Embodiment of 2,6-dimethyl-4-tert-butylphenylsulfurtrifluoride, a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Chlorine (Cl₂) was passed at 23 ml/min through a stirred mixture of 5.79g (15.0 mmol) of bis(2,6-dimethyl-4-tert-butylphenyl)disulfide and 8.7 g(58.1 mmol) of spray-dried potassium fluoride (KF) in 30 ml of dryacetonitrile cooled on an ice bath. After 1.18 L (52.5 mmol) of chlorinewas passed, nitrogen was passed through at the rate of 25 ml/min for twohours. The reaction mixture was filtered in a dry atmosphere. Thefiltrate was evaporated under vacuum (10-20 mmHg) at 20° C. and theresidue distilled at reduced pressure to give2,6-dimethyl-4-tert-butylphenylsulfur trifluoride (see Formula IV, Table4) (bp 68-70° C./0.1 mmHg (4.1 g, 55% yield, purity of >97.4%)).Spectral data was the same as shown in Example 2.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 3a Synthesis Embodiment of a Mixture of2,6-dimethyl-4-tert-butylphenylsulfur trifluoride and2,6-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride, FluorinatingAgents of the Present Invention

A 2000 mL fluoropolymer (PFA) vessel was charged with 40 gbis[2,6-dimethyl-4-tert-butylphenyl]disulfide (0.104 mol) and 60 g drypotassium fluoride (1.04 mol, dried under vacuum at 250° C. for threedays) in a dry box. The vessel was taken out from the dry box andconnected with the gas flow system. N₂ was passed through the vessel forabout 30 minutes at a rate of 64 mL/min. Approximately 200 mL dry CH₃CNwas then added to the mixture and the mixture allowed to cool on a bathof around −10° C. with N₂ flow continuing (64 mL/min). The reactionmixture was then bubbled with Cl₂ at the rate of 55 mL/min. The Cl₂bubbling was stopped after 148 min (8154 mL of Cl₂ (0.364 mol) wasbubbled). The reaction mixture changed from light yellow, to orange, andthen to pale yellow. The reaction mixture was slowly warmed to roomtemperature with N₂ flow (16 mL/min), and stirred overnight. Then, thereaction mixture was brought to the dry box and filtered. The filtratewas dried under vacuum to yield a light yellow solid. Distillation undervacuum (˜0.4 mmHg, 120˜130° C. for oil bath) yielded 43 g of theproducts, which were found by the NMR analysis to be a 93:7 (mol ratio)mixture of 2,6-dimethyl-4-tert-butylphenylsulfur trifluoride (formulaIV, Table 3) and 2,6-dimethyl-3-chloro-4-tert-butylphenylsulfurtrifluoride (formula IVa, Table 3).

2,6-dimethyl-4-tert-butylphenylsulfur trifluoride: Yield 76%; ¹H NMR(CD₃CN/Et₂O (1/1, v/v)), 7.29 (s, 1H, Ar—H), 7.25 (s, 1H, Ar—H), 2.69(d, J=5.5 Hz, 3H, CH₃), 2.57 (br.s, 3H, CH₃), 1.33 (s, 9H, C(CH₃)₃); ¹⁹FNMR (CD₃CN/Et₂O (1/1, v/v)), 53.2 (d, J=67 Hz, 2F, SF₂), −57.5 (t, J=67Hz, 1F, SF).

2,6-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride: Yield 5.7%;¹H NMR (CD₃CN/Et₂O=1/1 (v/v)), 7.39 (s, 1H, Ar—H), the CH₃ protons ofthe minor product were overlapped by the CH₃ protons of the mainproduct, 1.52 (s, 9H, C(CH₃)₃); ¹⁹F NMR (CD₃CN/Et₂O (1/1, v/v)), 54.2(d, J=63 Hz, 1.6 F, SF₂), 53.6 (d, J=56 Hz, 0.4 F, SF₂), −53.4 (t, J=56Hz, 0.2 F, SF), −56.0 (t, J=63 Hz, 0.4 F, SF).

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 3b Synthesis Embodiment of2,6-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride, aFluorinating Agent of the Present Invention

In a 100 mL fluoropolymer flask equipped with a magnetic stirring barand a fluoropolymer condenser, 4.89 g (0.01 mol) ofbis(2,6-dimethyl-3-chloro-4-tert-butylphenyl) disulfide was suspended in20 mL of anhydrous 1,1,2-trichlorotrifluoroethane under nitrogenatmosphere. AgF₂ (9.92 g, 0.13 mol) was added in portion wise. Thereaction started and heat was generated during addition of the AgF₂.After complete addition of AgF₂, the reaction was heated to 40° C. for 5min and then stirred at room temperature for 0.5 h. All black powder ofAgF₂ changed to yellow colored powder (AgF). Under nitrogen atmosphere,the solution was transferred to a 50 mL glass distillation flask, theyellow powder was washed with 15 mL of anhydrous1,1,2-trichlorotrifluoroethane. Distillation at reduced pressure gave4.7 g of 2,6-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride(formula IVa, Table 3): Yield: 4.7 g (78%); bp 105-106° C./0.4 mmHg(bath temperature 125° C.); ¹H NMR (CDCl₃) δ 1.50 (s, 9H, C(CH₃)₃), 2.67(s, 6H, CH₃), 7.23 (s, 1H, Ar—H); ¹⁹F NMR (THF-d₈) δ 49.95 (1.6 F, d,J=63 Hz, SF₂), 47.45 (0.4 F, d, J=54 Hz, SF₂), −59.68 (0.4 F, t, J=54Hz, SF), −60.27 (1.6 F, t, J=63 Hz, SF); ¹³C NMR (CDCl₃) δ 18.00, 32.37,41.28, 131.90, 135.84, 144.85, 148.67.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Experiment 3c Synthesis Embodiment of2,6-dimethyl-3,5-dichloro-4-tert-butylphenylsulfur trifluoride, aFluorinating Agent of the Present Invention

A fluoropolymer flask was charged with 5.24 g (0.01 mol) ofbis(2,6-dimethyl-3,5-dichloro-4-tert-butylphenyl)disulfide, 5.8 g (0.1mol) of dry potassium fluoride and 30 ml of anhydrous acetonitrile.Chlorine gas (0.035 mol, 784 mL) was bubbled through the mixture at arate of 20 mL/min at ice water temperature. The ice bath was removed andthe reaction mixture stirred at room temperature for 2 h. The reactionmixture was filtered and acetonitrile removed at reduced pressure.Distillation of the product at reduced pressure gave 5.05 g (80%) of2,6-dimethyl-3,5-dichloro-4-tert-butylphenylsulfur trifluoride (seeformula IVb, Table 3) as a colorless liquid: Bp 113-115° C./0.4 mmHg(bath temperature 130° C.); ¹H NMR (CDCl₃) δ 1.73 (s, 9H, C(CH₃)₃), 2.69(s, 6H, CH₃): ¹⁹F NMR (CDCl₃) δ 53.80 (br.s, 2F, SF₂), −51.49 (br.s, 1F,SF); ¹³C NMR (CDCl₃) δ 18.00, 32.37, 41.28, 131.90, 135.84, 144.85,148.67.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 4 Synthesis Embodiment of 4-tert-butylphenylsulfur trifluoride,a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Using a synthesis procedure similar to the one described in Example 2,4-tert-butylphenylsulfur trifluoride was prepared. However, unlike inExample 2, bis(4-tert-butylphenyl)disulfide was added to the slurryinstead of the bis(2,6-dimethyl-4-tert-butylphenyl) disulfide.

The above described synthesis procedure produced4-tert-butylphenylsulfur trifluoride (see Formula V, Table 3). Thephysical and spectral data of the material are as follows: Bp 76° C./1mmHg; ¹⁹F NMR (CD₃CN) δ 56.57 (br.s, 2F), −39.24 (br.s, 1F); ¹H NMR(CD₃CN) δ 7.95 (d, J=8.3 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 1.33 (s, 9H);¹³C NMR (CD₃CN) δ 158.17 (s), 143.11 (s), 126.46 (s), 124.24 (s), 35.07(s), 30.31 (s); MS (EI) m/z 222.1 (M⁺, 0.4), 203.1 (M⁺-F, 8.8), 137.1(M⁺-SF₂—CH₃, 100.0); HRMS (EI) for C₁₀H₁₃F₃S (M⁺): found 222.068288.calcd 222.069007.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 5 Synthesis Embodiment of 4-tert-butylphenylsulfur trifluoride,a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Using a synthesis procedure similar to the one described in Example 3,4-tert-butylphenylsulfur trifluoride was prepared. However, unlike inExample 3, bis(4-tert-butylphenyl)disulfide was used as a startingmaterial. A yield of 67% was obtained.

The physical and spectral data for the product produced in this Examplewas the same as shown in Example 4.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 6 Synthesis Embodiment of 2,4,6-trimethylphenylsulfurtrifluoride, a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Using a synthesis procedure similar to the one described in Example 2,2,4,6-trimethylphenylsulfur trifluoride was prepared. However, unlike inExample 2, bis(2,4,6-trimethylphenyl)disulfide was added to the slurryinstead of the bis(2,6-dimethyl-4-tert-butylphenyl)disulfide.

The above described synthesis procedure produced2,4,6-trimethylphenylsulfur trifluoride (see Formula VI, Table 3). Thephysical and spectral data of the material are as follows: Bp 58-59°C./1 mmHg; ¹⁹F NMR (THF-d₈) δ 53.13 (d, J=52.0 Hz, 2F), −57.40 (t,J=43.4 Hz, 1F); ¹H NMR (CD₃CN/THF-d₈) δ 6.97 (s, 1H), 6.94 (s, 1H), 2.59(s, 3H), 2.47 (s, 3H), 2.24 (s); ¹³C NMR (THF-d₈) δ 142.33 (s), 141.83(s), 134.20 (s), 133.03 (s), 130.86 (s), 129.99 (s), 20.07 (s), 18.83(s), 18.70 (s); MS (EI) m/z 208.0 (M⁺, 5.0), 189.0 (M⁺-F, 15.4), 138.0(M⁺-SF₂, 100.0); HRMS (EI) for C₉H₁₁F₃S (M⁺): found 208.052377. calcd208.053357.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 7 Synthesis Embodiment of 2,4,6-trimethylphenylsulfurtrifluoride, a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Using a synthesis procedure similar to the one described in Example 3,2,4,6-trimethylphenylsulfur trifluoride was prepared. However, unlike inExample 2, bis(2,4,6-trimethylphenyl)disulfide was used as a startingmaterial. A yield of 58% was obtained.

The physical and spectral data for the product produced in this Examplewas the same as shown in Example 6.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 8 Synthesis Embodiment of 2,4-dimethylphenylsulfur trifluoride,a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Using a synthesis procedure similar to the one described in Example 2,2,4-dimethylphenylsulfur trifluoride was prepared. However, unlike inExample 2, bis(2,4-dimethylphenyl)disulfide was added to the slurryinstead of the bis(2,6-dimethyl-4-tert-butylphenyl)disulfide. A yield of59% was obtained.

The above described synthesis procedure produced2,4-dimethylphenylsulfur trifluoride (see Formula VII, Table 3). Thephysical and spectral data of the material are as follows: Bp 56° C./1mmHg; ¹⁹F NMR (CD₃CN/THF-d₈) δ 52.44 (d, J=60.7 Hz, 2F), −57.75 (t,J=60.7 Hz, 1F); ¹H NMR (CD₃CN) δ 7.90 (d, J=8.2 Hz, 1H), 7.29 (d, J=8.2Hz, 1H), 7.18 (s, 1H), 2.62 (s, 3H), 2.42 (s, 3H); ¹³C NMR(CD₃CN/THF-d₈) δ 144.76 (s), 134.30 (s), 133.80 (s), 131.92 (s), 131.70(s), 129.79 (s), 19.09 (s), 18.92 (s); MS (EI) m/z 194.0 (M⁺, 6.9),175.0 (M⁺-F, 22.4), 124.0 (M⁺-SF₂, 100.0); HRMS (EI) for C₈H₉F₃S (M⁺):found 194.036951. calcd 194.037707.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 9 Synthesis Embodiment of 2,4-dimethylphenylsulfur trifluoride,a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Using a synthesis procedure similar to the one described in Example 3,2,4-dimethylphenylsulfur trifluoride was prepared. However, unlike inExample 3, bis(2,4-dimethylphenyl)disulfide was used as a startingmaterial. A yield of 71% was obtained.

The physical and spectral data for the product in this Example were thesame as shown in Example 8.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 10 Synthesis Embodiment of 2,5-dimethylphenylsulfur trifluoride,a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Using a synthesis procedure similar to the one described in Example 3,2,5-dimethylphenylsulfur trifluoride was prepared. However, unlike inExample 3, bis(2,5-dimethylphenyl)disulfide was used as a startingmaterial. A yield of 60% was obtained.

The above described synthesis procedure produced2,5-dimethylphenylsulfur trifluoride (see Formula VIII, Table 3). Thephysical and spectral data of the material are as follows: Bp 76-79°C./3 mmHg; ¹⁹F NMR (CD₃CN) δ 60.89 (br.s, 2F), −57.15 (br.s, 1F); ¹H NMR(CD₃CN) δ 7.90 (s, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.26 (d, J=7.7 Hz, 1H),2.66 (s, 3H), 2.49 (s, 3H); MS (EI) m/z 105.1 (M⁺-SF₃, 100.0), 194.0(M⁺, 8.0); HRMS (EI) for C₈H₉F₃S (M⁺): found 194.037412. calcd194.037707.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 11 Synthesis Embodiment of 2,6-dimethylphenylsulfur trifluoride,a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Using a synthesis procedure similar to the one described in Example 3,2,6-dimethylphenylsulfur trifluoride was prepared. However, unlike inExample 3, bis(2,6-dimethylphenyl)disulfide was used as a startingmaterial. A yield of 75% was obtained.

The above described synthesis procedure produced2,6-dimethylphenylsulfur trifluoride (see Formula IX, Table 3). Thephysical and spectral data of the material are as follows: Bp 73-75°C./3.5 mmHg; ¹⁹F NMR (CD₃CN) δ 53.51 (br.s, 2F), −55.99 (br.s, 1F); ¹HNMR (CD₃CN) δ 7.41 (t, J=7.7 Hz, 1H), 7.23 (br.s, 2H), 2.86 (s, 3H),2.70 (s, 3H); MS (EI) m/z 105.1 (M⁺-SF₃, 100.0), 194.0 (M⁺, 7.0); HRMS(EI) for C₈H₉F₃S (M⁺): found 194.037035. calcd 194.037707.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 12 Synthesis Embodiment of 4-fluorophenylsulfur trifluoride, aFluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Using a synthesis procedure similar to the one described in Example 2,4-fluorophenylsulfur trifluoride was prepared. However, unlike inExample 2, bis(4-fluorophenyl) disulfide was used as a startingmaterial. A yield of 56% was obtained.

The above described synthesis procedure produced 4-fluorophenylsulfurtrifluoride (see Formula X, Table 3). The physical and spectral data ofthe material are as follows: Bp 39-40° C./2 mmHg; ¹⁹F NMR (CD₃CN/THF-d₈)δ 58.14 (d, J=60.7 Hz, 2F), −37.28 (t, J=32.0 Hz, 1F), −104.42 (s, 1F);¹H NMR (CD₃CN/THF-d₈) δ 8.40 (dd, J=5.8, 8.6 Hz, 2H), 7.66 (t, J=8.6 Hz,2H); ¹³C NMR (CD₃CN/THF-d₈) δ 165.98 (d, J=255.0 Hz), 142.41 (d, J=15.2Hz), 130.66 (d, J=8.0 Hz), 116.69 (d, J=23.1 Hz); MS (EI) m/z 184.0(M⁺-F, 0.1), 165.0 (M⁺-F, 18.5), 114.0 (M⁺-SF₂, 100.0); HRMS (EI) forC₆H₄F₄S (M⁺): found 183.996675. calcd 183.996985.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 13 Synthesis Embodiment of 4-chlorophenylsulfur trifluoride, aFluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Using a synthesis procedure similar to the one described in Example 2,4-chlorophenylsulfur triflouride was prepared. However, unlike Example2, bis(4-chlorophenyl) disulfide was used as a starting material. Ayield of 32% was obtained.

The above described synthesis procedure produced 4-chlorophenylsulfurtrifluoride (see Formula XI, Table 3). The physical and spectral data ofthe material are as follows: Bp 55-56° C./1 mmHg; ¹⁹F NMR (CD₃CN/THF-d₈)δ 58.20 (d, J=60.7 Hz, 2F), −39.44 (t, J=60.7 Hz, 1F); ¹H NMR(CD₃CN/THF-d₈) δ 8.19 (d, J=7.6 Hz, 2H), 7.82 (d, J=7.6 Hz, 2H); ¹³C NMR(CD₃CN) δ 144.65 (s), 140.00 (s), 129.56 (s), 128.38 (s); MS (EI) m/z201.9 (M⁺, 0.3), 199.9 (M⁺, 0.9), 130.0 (M⁺-SF₂, 100.0), HRMS (EI) forC₆H₄ClF₃S (M⁺): found 201.965496. calcd. 201.964484, and found199.967032. calcd 199.967434.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 14 Synthesis Embodiment of 3-methyl-4-chlorophenylsulfurtrifluoride, a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

Chlorine (Cl₂) was passed at a rate of 30 mL/min into a stirred mixtureof 4.44 g (18 mmol) of bis(3-methylphenyl)disulfide and 15.7 g (270mmol) of spray-dried KF. The stirred mixture also included 100 ml of dryacetonitrile. The mixture was stirred on an ice bath. After 1.92 L (85.7mmol) of chlorine was passed through the mixture, nitrogen was thenpassed through the mixture for 3 hours at room temperature. The reactionmixture was then filtered in a dry atmosphere and the filtrate wasevaporated under reduced pressure without heating.

Residue was distilled at reduced pressure to give 4.71 g of the compoundas shown in Formula XII, Table 3. A yield of 61% was obtained. Thephysical and spectral data of the material are as follows: Bp 72-75°C./4 mmHg; ¹⁹F NMR (CDCl₃) δ 57.9 (br.s, 2F), −37.7 (br.s, 1F); ¹H NMR(CDCl₃) δ 7.85 (br.s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.46 (d, J=8.6 Hz,1H), 2.30 (s, 3H); MS (EI) m/z 125.0 (M⁺-SF₃, 100.0), 214 (M⁺, 1.2);HRMA (EI) for C₇H₆ClF₃S (M⁺): found 215.980817, calcd 215.980134, andfound 213.983426, calcd 213.983085.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 15 Synthesis Embodiment of 2,4,6-tri(isopropyl)phenylsulfurtrifluoride, a Fluorinating Agent of the Present Invention

The following reaction scheme is provided as illustrative for thisexample:

In a similar way as in Example 2, 2,4,6-tri(isopropyl)phenylsulfurtrifluoride was synthesized frombis[2,4,6-tris(isopropyl)phenyl]disulfide. A yield of 79% was obtained.The purification of this compound was achieved by sublimation at 70°C./0.1 mmHg. The formula is shown as Formula XIII, Table 3.

The physical and spectral data of the material are shown in thefollowing: Mp 87.3° C. (by DSC); ¹⁹F NMR (THF-d₈) δ 60.68 (d, J=52.0 Hz,2F), −53.88 (t, J=52.0 Hz, 1F); ¹H NMR (CD₃CN) δ 7.33 (s, 1H), 7.27 (s,1H), 3.89 (m, 1H), 3.44 (m, 1H), 2.95 (septet, J=7.1 Hz, 1H), 1.29 (d,J=6.6 Hz, 12H), 1.24 (d, J=7.1 Hz, 6H); MS (EI) m/z 149.0 (M⁺+1-2F,100.0), 292.2 (M⁺, 1.2); HRMS (EI) for C₁₅H₂₃F₃S (M⁺): found 292.145944,calcd 292.147257.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 15a Synthesis Embodiment of 2,6-di(methoxymethyl)phenylsulfurtrifluoride, a Fluorinating Agent of the Present Invention

Using a synthesis procedure similar to the one described in Example 3b,2,6-bis(methoxymethyl)phenylsulfur trifluoride (formula XIV, Table 3)was prepared. However, unlike Example 3b,bis[2,6-bis(methoxymethyl)phenyl]disulfide was used as a startingmaterial. A yield of 77% was obtained. The physical and spectral data ofthe material are as follows: Bp 110° C./0.4 mmHg (bath temperature 130°C.); ¹H NMR (CDCl₃) δ 3.41 (s, 6H, OCH₃), 4.83 (br.s, 4H, CH₂), 7.42 (m,3H, Ar—H); ¹⁹F NMR (CDCl₃) δ 50.37 (br.s, 2F, SF₂), −53.1 (br.s, 1F,SF); ¹³C NMR (CDCl₃) δ 58.4, 71.7, 128.3, 131.4, 136.4, 144.6. Elementalanalysis: Calcd for C₁₀H₁₃F₃O₂S: C, 47.24%; H, 5.15%. Found: C, 47.02%;H, 5.12%.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 15b Synthesis Embodiment of2,6-bis(methoxymethyl)-4-tert-butylphenylsulfur trifluoride, aFluorinating Agent of the Present Invention

Using a synthesis procedure similar to the one described in Example 3b,2,6-bis(methoxymethyl)-4-tert-butylphenylsulfur trifluoride (formula XV,Table 3) was prepared. However, unlike Example 3b,bis[2,6-bis(methoxymethyl)-4-tert-butylphenyl]disulfide was used as astarting material. A yield of 75% was obtained. The physical andspectral data of the material are as follows: Bp 128-130° C./0.4 mmHg(bath temperature 150° C.); ¹H NMR (CDCl₃) δ 1.34 (s, 9H, C(CH₃)₃), 3.46(s, 6H, OCH₃), 4.82 (br.s, 4H, CH₂), 7.41 (s, 2H, Ar—H); ¹⁹F NMR (CDCl₃)δ 48.68 (br.s, 2F, SF₂), −53.37 (br.s, 1F, SF); ¹³C NMR (CDCl₃) δ 31.0,35.1, 58.5, 76.7, 125.4, 136.2, 141.5, 155.0. Elemental analysis: Calcdfor C₁₄H₂₁F₃O₂S: C, 54.18%; H, 6.82%. Found: C, 54.31%; H, 6.86%.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 15c Synthesis Embodiment of2,6-bis(methoxymethyl)-4-tert-butylphenylsulfur trifluoride, aFluorinating Agent of the Present Invention

A 500 mL fluoropolymer flask was charged with 22.4 g (0.044 mol) ofbis[2,6-bis(methoxymethyl)-4-tert-butylphenyl]disulfide, 25.5 g (0.44mol) of dry potassium fluoride and 100 mL of anhydrous acetonitrile. Themixture was cooled to 0° C. and chlorine gas (0.15 mol, 3360 mL) bubbledthrough at a rate of 35 mL/min. The reaction mixture was stirred at 0°C. for another 1 h, followed by stirring at room temperature for 1 h.The reaction mixture was filtered and acetonitrile removed at reducedpressure at room temperature. The resultant liquid was distilled atreduced pressure to give 24 g of2,6-di(methoxymethyl)-4-tert-butylphenylsulfur trifluoride (formula XV,Table 3). Yield: 88%. The spectral data are as shown in Example 15b.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 15d Synthesis Embodiment of2,6-bis(ethoxymethyl)-4-tert-butylphenylsulfur trifluoride, aFluorinating Agent of the Present Invention

A fluoropolymer flask was charged with 3.14 g (6.0 mmol) ofbis[2,6-bis(ethoxymethyl)-4-tert-butylphenyl]disulfide, 18.2 g (120mmol) of dry cesium fluoride and 35 mL of anhydrous acetonitrile.Chlorine gas (16.00 mmol, 538 mL) was bubbled at the rate of 15 mL/minat 20° C. (water bath temperature). After passing chlorine, water bathwas removed and mixture was stirred at room temperature for 1 hour. Thesolution was transferred by decantation under nitrogen atmospherefollowed by washing with 15 mL of anhydrous acetonitrile. Acetonitrilewas removed at room temperature and product was purified by distillationat reduced pressure to give 2.5 g (65%) of2,6-bis(ethoxymethyl)-4-tert-butylphenylsulfur trifluoride (formula XVI,Table 3) as a light yellow liquid: Bp 118° C./0.2 mm (bathtemperature=140° C.); ¹H NMR (CDCl₃) δ 1.32 (6H, CH₂CH₃), 1.32 (s, 9H,C(CH₃)₃), 3.60 (q, 4H), 4.89 (s, 4H), 7.54 (s, 2H, Ar—H); ¹⁹F NMR(CDCl₃) δ 48.77 (br.s, 2F, SF₂), −53.11 (br.s, 1F, SF); ¹³C-NMR (CDCl₃)δ 15.12, 31.02, 35.05, 66.29, 66.48, 125.33, 136.71, 154.89, 156.97.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 15e Synthesis Embodiment of2,6-bis(isopropoxyethyl)-4-tert-butylphenylsulfur trifluoride, aFluorinating Agent of the Present Invention

Using a synthesis procedure similar to the one described in Example 15d,2,6-bis(isopropoxymethyl)-4-tert-butylphenylsulfur trifluoride (formulaXVII, Table 3) was prepared. However, unlike Example 15d,bis[2,6-bis(isopropoxymethyl)-4-tert-butylphenyl]disulfide was used as astarting material. A yield of 61% was obtained. The physical andspectral data of the material are as follows: colorless liquid; bp 120°C./0.2 mmHg (bath temperature=145° C.); ¹H NMR (CDCl₃) δ 1.24 (d, J=6Hz, 12H, CH₃), 1.32 (s, 9H, C(CH₃)₃), 3.75 (septet, J=6.0 Hz, 2H, CH),4.80 (br.s, 4H, CH₂), 7.55 (s, 2H, Ar—H); ¹⁹F NMR (CDCl₃) δ 48.73 (br.s,2F, SF₂), −52.86 (br.s, 1F, SF); ¹³C NMR (CDCl₃) δ 21.99, 31.02, 35.05,66.51, 71.93, 125.76, 139.50, 141.75, 154.62.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 15f Synthesis Embodiment of2,6-bis(isobutoxymethyl)-4-tert-butylphenylsulfur trifluoride, aFluorinating Agent of the Present Invention

Using a synthesis procedure similar to the one described in Example 15d,2,6-bis(isobutoxymethyl)-4-tert-butylphenylsulfur trifluoride (formulaXVIII, Table 3) was prepared. However, unlike Example 15d,bis[2,6-bis(isobutoxymethyl)-4-tert-butylphenyl]disulfide was used as astarting material. A yield of 60% was obtained. The physical andspectral data of the material are as follows: Colorless oil; bp 130°C./0.2 mmHg (bath temperature=150° C.); ¹H NMR (CDCl₃) δ 0.97 (d, 12H,J=6 Hz, CH₃), 1.33 (s, 9H, C(CH₃)₃), 1.97 (m, 2H, CH), 3.33 (m, 4H,OCH₂), 4.89 (br.s, 4H, ArCH₂), 7.56 (broad peak, 2H, Ar—H); ¹⁹F NMR(CDCl₃) δ 47.42 (broad peak, 2F, SF₂), −53.15 (broad peak, 1F, SF);¹³C-NMR (CDCl₃) δ 19.31, 28.62, 31.39, 35.08, 69.22, 77.90, 125.63,139.14, 154.82, 156.94.

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Example 15g Synthesis Embodiment of2,6-bis(tert-butoxymethyl)-4-tert-butylphenylsulfur trifluoride, aFluorinating Agent of the Present Invention

A fluoropolymer flask was charged with 4.05 g (6.0 mmol) ofbis[2,6-bis(tert-butoxymethyl)-4-tert-butylphenyl]disulfide, 18.2 g (120mmol) of dry cesium fluoride and 35 mL of anhydrous acetonitrile.Chlorine gas (16.00 mmol, 1.70 g, 538 ml) was bubbled at the rate of 15mL/min at 20° C. (water bath temperature). After passing chlorine, waterbath was removed and mixture was stirred at room temperature for 1 hour.The solution was transferred by decantation under nitrogen atmospherefollowed by washing with 15 mL of anhydrous acetonitrile. Acetonitrilewas removed at room temperature to give a residue, which was extractedwith anhydrous hexane. The hexane extract was evaporated to dryness,giving 3.3 g (70%) of2,6-bis(tert-butoxymethyl)-4-tert-butylphenylsulfur trifluoride (formulaXIX, Table 3) as a light yellow oil: ¹H NMR (CDCl₃) δ 1.27 (s, 9H), 1.32(s, 9H), 1.36 (s, 9H), 4.72 (s, 2H), 5.00 (s, 2H), 7.20 (s, 1H), 7.93(s, 1H); ¹⁹F NMR (CDCl₃) δ 47.38 (br.s, 2F, SF₂), −53.20 (br.s, 1F, SF);¹⁹F NMR (CDCl₃+THF (1:1)) δ 48.50 (2F, d, J=79 Hz, SF₂), −53.20 (1F, t,J=79 Hz, SF).

The present example illustrates the utility of the present invention forsynthesizing fluorinating agents that can be used to producefluorine-containing compounds.

Examples 16-25d Thermal Analysis of Substituted PhenylsulfurTrifluorides

Thermal analysis was performed on compounds IV, IVa, IVb, V-XV of thepresent invention and PhSF₃ and p-CH₃C₆H₄SF₃ (Table 4). Decompositiontemperature and exothermic heat (−ΔH) of each compound was determinedusing Differential Scanning Spectroscopy, i.e., using a DifferentialScanning Spectrometer (DSC).

The decomposition temperature is the temperature at which onset ofdecomposition begins, and the exothermic heat is the amount of heat thatresults from the compounds decomposition. In general, a higherdecomposition temperature and lower exothermic heat value providecompounds having greater thermal stability and provide greater safety.

Table 4 illustrates that the compounds of the present invention, thephenylsulfur trifluorides substituted with the alkyl group(s), a halogenatom(s), and/or the alkyl group(s) having ether linkage, show unexpectedand significant improvement in decomposition temperature and exothermicheat values over the useful conventional fluorinating agents (DAST andDeoxo-Fluor®). This data illustrates the improved thermal stability ofthe compounds of the invention and, as a result, the improved safety ofthe compounds of the invention over other useful conventionalfluorinating agents. Phenylsulfur trifluoride (PhSF₃) andp-methylphenylsulfur trifluoride (p-CH₃C₆H₄SF₃) have high decompositiontemperatures, but they have high exothermic heat and their fluorinationreactivity is low (see Examples below).

TABLE 4 Thermal Analysis Data of Substituted Phenylsulfur Trifluorides(Formulas IV~XV) and Prior Art PhSF₃, p-CH₃C₆H₄SF₃, DAST andDeoxo-Fluor ® Decomposition Compound temp. (° C.) −ΔH (J/g) Ex. 16 IV;R^(1a) = R^(1b) = CH₃, R^(2a) = R^(2b) = H, R³ = C(CH₃)₃ 232 544 Ex. 16aIVa; R^(1a) = R^(1b) = CH₃, R^(2a) = Cl, R^(2b) = H, R³ = C(CH₃)₃ 227520 Ex. 16b IVb; R^(1a) = R^(1b) = CH₃, R^(2a) = R^(2b) = Cl, R³ =C(CH₃)₃ 238 392 Ex. 17 V; R^(1a) = R^(1b) = R^(2a) = R^(2b) = H, R³ =C(CH₃)₃ 319 700 Ex. 18 VI; R^(1a) = R^(1b) = CH₃, R^(2a) = R^(2b) = H,R³ = CH₃ 209 462 Ex. 19 VII; R^(1a) = CH₃ R^(1b) = H, R^(2a) = R^(2b) =H, R³ = CH₃ 222 625 Ex. 20 VIII; R^(1a) = CH₃, R^(1b) = H, R^(2a) = H,R^(2b) = CH₃, R³ = H 228 486 Ex. 21 IX; R^(1a) = R^(1b) = CH₃, R^(2a) =R^(2b) = R³ = H 225 595 Ex. 22 X; R^(1a) = R^(1b) = R^(2a) = R^(2b) = H,R³ = F 297 368 Ex. 23 XI; R^(1a) = R^(1b) = R^(2a) = R^(2b) = H, R³ = Cl311 458 Ex. 24 XII; R^(1a) = R^(1b) = H, R^(2a) = CH₃, R^(2b) = H, R³ =Cl 299 391 Ex. 25 XIII; R^(1a) = R^(1b) = CH(CH₃)₂, R^(2a) = R^(2b) = H,R³ = CH(CH₃)₂ 215 552 Ex. 25a XIV; R^(1a) = R^(1b) = CH₂OCH₃, R^(2a) =R^(2b) = H, R³ = H 175 585 Ex. 25b XV; R^(1a) = R^(1b) = CH₂OCH₃, R^(2a)= R^(2b) = H, R³ = C(CH₃)₃ 192 674 Ex. 25c PhSF₃ 305 826 Ex. 25dp-CH₃C₆H₄SF₃ 274 1096 (C₂H₅)₂N—SF₃ (DAST) ~140 1700 (CH₃OCH₂CH₂)₂N—SF₃(Deoxo-Fluor ®) ~140 1100

Examples 26-55 Fluorination of Target Compounds Using the Compounds ofthe Present Invention

Many procedures are provided for fluorinating a target compound usingthe fluorinating agents of the present invention. Ten procedures aredescribed as procedures A-J:

Procedure A: In a 10 mL fluoropolymer (PFA)-bottle (equipped with an N₂inlet tube, septum and magnetic stir bar): 65 mg of benzyl alcohol(0.604 mmol) was added to a solution of 166 mg2,6-dimethyl-4-tert-butylphenylsulfur trifluoride (formula IV) (0.664mmol) in 3 mL anhydrous CH₂Cl₂. The addition was performed at roomtemperature under a stream of N₂. The mixture was allowed to stir atroom temperature. The progress of the reaction was monitored by gaschromatography (GC). After 2 hours a ¹⁹F-NMR analysis was performedindicating that benzyl fluoride was obtained (88% yield).

Procedure B: In a 5 mL fluoropolymer-bottle (equipped with an N₂ inlettube, septum and magnetic stir bar): 42 mg isovaleraldehyde (0.491 mmol)was added to a solution of 135 mg 2,6-dimethyl-4-tert-butylphenylsulfurtrifluoride (formula IV) (0.540 mmol) in 0.5 mL anhydrous CH₂Cl₂. Theaddition was performed at room temperature under a stream of N₂. Themixture was allowed to stir at room temperature. The progress of thereaction was monitored by GC. After 24 hours a ¹⁹F-NMR analysis wasperformed indicating that 1,1-difluoro-3-methylbutane was obtained (95%yield).

Procedure C: In a 5 mL fluoropolymer-bottle (equipped with an N₂ inlettube, septum and magnetic stir bar): 40 mg cyclohexanone (0.405 mmol)was added to a solution of 172 mg 2,6-dimethyl-4-tert-butylphenylsulfurtrifluoride (formula IV) (0.688 mmol) in 0.5 mL anhydrous CH₂Cl₂. Theaddition was performed at room temperature under a stream of N₂. Ethanol(3.7 mg, 0.08 mmol) was added to the reaction and the reaction allowedto stir at room temperature. The progress of the reaction was monitoredby GC. After 24 hours a ¹⁹F-NMR analysis was performed indicating that1,1-difluorocyclohexane was obtained (74% yield).

The purpose of the addition of ethanol in Procedure C is to makehydrogen fluoride (HF), which accelerates the fluorination reaction as acatalyst. Ethanol reacts with the SF₃ fluorinating agent to HF togetherwith ethyl fluoride.

Procedure D: In a 1 mL fluoropolymer tube: 21 mg benzoic acid (0.170mmol) was added to 106 mg 2,6-dimethyl-4-tert-butylphenylsulfurtrifluoride (formula IV) (0.424 mmol). The addition was made at roomtemperature under a stream of N₂. The tube was then sealed and heated at100° C. The progress of the reaction was monitored by GC. After 2 hoursa ¹⁹F-NMR analysis was performed indicating that α,α,α-trifluorotoluenewas obtained (88% yield).

Procedure E: A 5 mL fluoropolymer vessel was charged with 1.0 g (4.55mmol) of p-heptylbenzoic acid and 3.4 g (13.65 mmol) of a 93:7 (molratio) mixture of 2,6-dimethyl-4-tert-butylphenylsulfur trifluoride(formula IV) and 2,4-dimethyl-3-chloro-4-tert-butylphenylsulfurtrifluoride (formula IVa), in a dry box. The reaction vessel was thenbrought out from the dry box. 1.0 mL of hydrogen fluoride pyridine (amixture of ˜70% of HF and ˜30% of pyridine) was slowly added into thereaction mixture under nitrogen. The reaction mixture was slowly heatedto 50° C., and kept at that temperature for 22 hours. The NMR analysisshowed that p-heptybenzotrifluoride was produced in 74% yield.

Procedure F: In a dry box, 0.500 g (2.72 mmol) of O-phenyl S-methyldithiocarbonate and 3.4 g (13.6 mmol) of a 93:7 (mol ratio) mixture of2,6-dimethyl-4-tert-butylphenylsulfur trifluoride (formula IV) and2,4-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride (formula IVa)were put in a 5 mL fluoropolymer vessel. The mixture was slowly heatedto 80° C. and maintained at the temperature for 19 hours. The NMRanalysis using a sample showed that phenyl trifluoromethyl ether wasproduced in 92% yield. ¹⁹F NMR for PhOCF₃ (CDCl₃): −58.22 (s, 3F, CF₃).

Procedure G: In a dry box, 0.912 g (6 mmol) of O-methyl thiobenzoate and1.8 g (7.2 mmol) of a 93:7 (mol ratio) mixture of2,6-dimethyl-4-tert-butylphenylsulfur trifluoride (formula IV) and2,4-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride (formula IVa)were put in a 5 mL fluoropolymer vessel. Then, the reaction mixture washeated to 100° C. under N₂ for 2 hours. The reaction mixture changedfrom initial light green to pink. The NMR analysis showed that methylphenyldifluoromethyl ether was produced in 95% yield. ¹⁹F NMR forPhCF₂OCH₃ (CDCl₃) δ −72.17 (s, 2F, CF₂).

Procedure H: In a dry box, 0.304 mg (2 mmol) of O-methyl thiobenzoatewas dissolved in 2 mL of dry CH₂Cl₂ in a 5 mL fluoropolymer vessel.Then, 0.6 g (2.4 mmol) of a 93:7 (mol ratio) mixture of2,6-dimethyl-4-tert-butylphenylsulfur trifluoride (formula IV) and2,4-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride (formula IVa)was added to the solution, and 15 mg (0.066 mmol) of SbCl₃ was added tothe reaction mixture. The reaction mixture was stirred under N₂ at roomtemperature for 26 hours. The NMR analysis showed that methylphenyldifluoromethyl ether was produced in 78% yield.

Procedure I: In a dry box, 0.31 g (1.58 mmol) of 2-phenyl-1,3-dithianewas dissolved in 2 mL anhydrous CH₂Cl₂ in a 5 mL fluoropolymer vessel.Then 1.0 g (4.0 mmol) of a 93:7 (mol ratio) mixture of2,6-dimethyl-4-tert-butylphenylsulfur trifluoride (formula IV) and2,4-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride (formula IVa)was added to the reaction mixture. Slight exothermic reaction occurred.The reaction mixture was then stirred at room temperature for 2 hoursunder N₂. The NMR analysis showed that difluoromethylbenzene wasproduced in 82% yield. ¹⁹F NMR for PhCF₂H (CDCl₃) δ −110.54 (d, J=60.7Hz, CF₂).

Procedure J: In a 15 mL fluoropolymer flask,2,6-dimethyl-4-tert-butylphenylsulfur trifluoride (0.625 g, 2.5 mmol)was dissolved in 5 mL of anhydrous CH₂Cl₂. A solution ofmeso-1,2-diphenyl-1,2-ethanediol (0.214 g, 1.0 mmol) in 5 mL ofanhydrous CH₂Cl₂ was added to the above stirred solution at roomtemperature. After 3 hours, C₁₂H₂₆F was added as standard, the ¹⁹F NMRanalysis showed that 1,2-difluoro-1,2-diphenylethane (PhCHFCHFPh) wasproduced in 97% yield and a trace (˜0.03%) of1,1-difluoro-2,2-diphenylethane (Ph₂CHCF₂H) was formed. Products werecharacterized by comparing to the spectroscopic data in literature (seeJournal of Fluorine Chem. Vol. 125, pp 1869-1872 (2004)).

Referring to Table 5: Examples 26-28, 28a, 29-32, 32a-f, 33-44, 44a, 54,55 and reactions with a known fluorinating agent (PhSF₃) (ComparisonExample 1) and a known and similar compound (p-CH₃C₆H₄SF₃) [J. Am. Chem.Soc., Vol. 84, pp 3058-3063 (1962)] (Comparison Example 2) were carriedout under the reaction conditions shown in Table 5 and according toprocedure A; Examples 45, 45a-c, 48, 48a,b, 49, 49a,b, and 50 werecarried out under the reaction conditions shown in Table 5 and accordingto procedure B; Examples 46, 46a,b, 47 and 47a,b were carried out underthe conditions shown in Table 5 and according to procedure C; andExamples 51, 51a, 52, 52a, 53, and 53a were carried out under theconditions shown in Table 5 and according to procedure D. The proceduresE, F, G, H and I are for Examples 49c, 55a, 55b, 55c and 55d,respectively. The Procedure J is for Examples 55e and 55f and ComparisonExamples 3 and 4.

TABLE 5 Fluorinations of Various Organic Target Compounds withSubstituted Phenylsulfur Trifluorides (Formulas IV, IVa, b, V~XVIII),Prior Art Compounds (PhSF₃ and p-CH₃C₆H₄SF₃), and ConventionalFluorinating Agents (DAST and Deoxo-Fluor ®). Phenyl- Fluorinated sulfurReaction conditions compounds trifluorides Organic compounds Solv, TempAdditive Time Chemical structure Yield Comp. PhSF₃ PhCH₂OH CH₂Cl₂ r.t. 2h PhCH₂F 25% Ex. 1 Comp. p- PhCH₂OH CH₂Cl₂ r.t. 2 h PhCH₂F 19% Ex. 2CH₃C₆H₄SF₃ Ex. 26 IV PhCH₂OH CH₂Cl₂ r.t. 2 h PhCH₂F 88% Ex. 27 V PhCH₂OHCH₂Cl₂ r.t. 2 h PhCH₂F 52% Ex. 28 VI PhCH₂OH CH₂Cl₂ r.t. 2 h PhCH₂F 38%Ex. 28a VII PhCH₂OH CH₂Cl₂ r.t. 2 h PhCH₂F 55% Ex. 29 VIII PhCH₂OHCH₂Cl₂ r.t. 2 h PhCH₂F 46% Ex. 30 IX PhCH₂OH CH₂Cl₂ r.t. 2 h PhCH₂F 40%Ex. 31 XI PhCH₂OH CH₂Cl₂ r.t. 2 h PhCH₂F 37% Ex. 32 XIII PhCH₂OH CH₂Cl₂r.t. 2 h PhCH₂F 46% Ex. 32a IVb PhCH₂OH CH₂Cl₂ r.t. 2 h PhCH₂F 90% Ex.32b XIV PhCH₂OH CH₂Cl₂ r.t. 2 h PhCH₂F 95% Ex. 32c XV PhCH₂OH CH₂Cl₂r.t. 2 h PhCH₂F 90% Ex. 32d XVI PhCH₂OH CH₂Cl₂ r.t. 2 h PhCH₂F 78% Ex.32e XVII PhCH₂OH CH₂Cl₂ r.t. 2 h PhCH₂F 83% Ex. 32f XVIII PhCH₂OH CH₂Cl₂r.t. 2 h PhCH₂F 93% Ex. 33 IV n-C₁₂H₂₅OH CH₂Cl₂ r.t. 6 h n-C₁₂H₂₅F 91%Ex. 34 V n-C₁₂H₂₅OH CH₂Cl₂ r.t. 6 h n-C₁₂H₂₅F 77% Ex. 35 VI n-C₁₂H₂₅OHCH₂Cl₂ r.t. 6 h n-C₁₂H₂₅F 61% Ex. 36 VII n-C₁₂H₂₅OH CH₂Cl₂ r.t. 6 hn-C₁₂H₂₅F 68% Ex. 37 X n-C₁₂H₂₅OH CH₂Cl₂ r.t. 6 h n-C₁₂H₂₅F 66% Ex. 38XI n-C₁₂H₂₅OH CH₂Cl₂ r.t. 6 h n-C₁₂H₂₅F 66% Ex. 39 IV n-C₁₀H₂₁CH(OH)CH₃CH₂Cl₂ r.t. 6 h n-C₁₀H₂₁CHFCH₃ 75% Ex. 40 V n-C₁₀H₂₁CH(OH)CH₃ CH₂Cl₂r.t. 6 h n-C₁₀H₂₁CHFCH₃ 72% Ex. 41 VI n-C₁₀H₂₁CH(OH)CH₃ CH₂Cl₂ r.t. 6 hn-C₁₀H₂₁CHFCH₃ 70% Ex. 42 VII n-C₁₀H₂₁CH(OH)CH₃ CH₂Cl₂ r.t. 6 hn-C₁₀H₂₁CHFCH₃ 54% Ex. 43 X n-C₁₀H₂₁CH(OH)CH₃ CH₂Cl₂ r.t. 6 hn-C₁₀H₂₁CHFCH₃ 49% Ex. 44 XI n-C₁₀H₂₁CH(OH)CH₃ CH₂Cl₂ r.t. 6 hn-C₁₀H₂₁CHFCH₃ 47% Ex. 44a XV n-C₁₀H₂₁CH(OH)CH₃ CH₂Cl₂ r.t. 6 hn-C₁₀H₂₁CHFCH₃ 77% Ex. 45 IV (CH₃)₂CHCH₂CHO CH₂Cl₂ r.t. 1 day(CH₃)₂CHCH₂CF₂H 95% Ex. 45a XIV PhCHO CH₂Cl₂ r.t. 4 h PhCF₂H 84% Ex. 45bXV PhCHO CH₂Cl₂ r.t. 4 h PhCF₂H 96% Ex. 45c XVII PhCHO CH₂Cl₂ r.t. 2 hPhCF₂H 80% Ex. 46 IV Cyclohexanone CH₂Cl₂ r.t. EtOH(HF) 1 day1,1-diF-cyclohexane 74% Ex. 46a XIV Cyclohexanone CH₂Cl₂ r.t. EtOH(HF) 6h 1,1-diF-cyclohexane 70% Ex. 46b XV Cyclohexanone CH₂Cl₂ r.t. EtOH(HF)6 h 1,1-diF-cyclohexane 72% Ex. 47 IV n-C₁₁H₂₃COCH₃ CH₂Cl₂ r.t. EtOH(HF)1 day n-C₁₁H₂₃CF₂CH₃ 100%  Ex. 47a XIV n-C₁₁H₂₃COCH₃ CH₂Cl₂ r.t.EtOH(HF) 1 day n-C₁₁H₂₃CF₂CH₃ 100%  Ex. 47b XV n-C₁₁H₂₃COCH₃ CH₂Cl₂ r.t.EtOH(HF) 1 day n-C₁₁H₂₃CF₂CH₃ 100%  Ex. 48 IV PhCOOH CH₂Cl₂ r.t. 2 dayPhCOF 100%  Ex. 48a XIV PhCOOH CH₂Cl₂ r.t. 1 day PhCOF 100%  Ex. 48b XVPhCOOH CH₂Cl₂ r.t. 1 day PhCOF 100%  Ex. 49 IV n-C₁₁H₂₃COOH CH₂Cl₂ r.t.1 day n-C₁₁H₂₃COF 97% Ex. 49a XIV n-C₁₁H₂₃COOH CH₂Cl₂ r.t. 1 dayn-C₁₁H₂₃COF 100%  Ex. 49b XV n-C₁₁H₂₃COOH CH₂Cl₂ r.t. 1 day n-C₁₁H₂₃COF100%  Ex. 49c IV (93%) + p-(n-C₇H₁₅)C₆H₄COOH HF/py 50° C. HF/py 22 hp-(n-C₇H₁₅)C₆H₄CF₃ 74% IVa (7%) Ex. 50 IV PhCOCl CH₂Cl₂ r.t. 2 day PhCOF51% Ex. 51 IV PhCOOH Non 100° C. 2 h PhCF₃ 89% Ex. 51a XIV PhCOOH Non100° C. 2 h PhCF₃ 50% Ex. 52 IV p-(n-C₇H₁₅)C₆H₄COOH Non 100° C. 2 hp-(n-C₇H₁₅)C₆H₄CF₃ 88% Ex. 52a XIV p-(n-C₇H₁₅)C₆H₄COOH Non 100° C. 2 hp-(n-C₇H₁₅)C₆H₄CF₃ 53% Ex. 53 IV n-C₁₁H₂₃COOH Non 100° C. 2 hn-C₁₁H₂₃CF₃ 55% Ex. 53a XIV n-C₁₁H₂₃COOH Non 100° C. 2 h n-C₁₁H₂₃CF₃ 60%Ex. 54 IV PhSCH₃ CH₂Cl₂ r.t. 20 min PhSCH₂F 61% Ex. 55 IV PhSOCH₃ CH₂Cl₂r.t. 24 h PhSCH₂F 41% Ex. 55a IV (93%) + PhOC(═S)SCH₃ Non 60° C. 15 hPhOCF₂OCH₃ 86% IVa (7%) Ex. 55b IV (93%) + PhC(═S)OCH₃ Non 100° C. 2 hPhCF₂OCH₃ 95% IVa (7%) Ex. 55c IV (93%) + PhC(═S)OCH₃ CH₂Cl₂ r.t. SbCl₃26 h PhCF₂OCH₃ 78% IVa (7%) Ex. 55d IV (93%) + IVa (7%)

CH₂Cl₂ r.t. 2 h PhCF₂H 82% Ex. 55e IV PhCH(OH)CH(OH)Ph CH₂Cl₂ r.t. 3 hPhCHFCHFPh 97% Ph₂CHCF₂H ~0.03%   Ex. 55f XV PhCH(OH)CH(OH)Ph CH₂Cl₂r.t. 24 h PhCHFCHFPh 98.5%  Ph₂CHCF₂H ~0.04%   Comp. DASTPhCH(OH)CH(OH)Ph CH₂Cl₂ r.t. 3 h PhCHFCHFPh 51% Ex.3 Ph₂CHCF₂H 13% Comp.Deoxo- PhCH(OH)CH(OH)Ph CH₂Cl₂ r.t. 3 h PhCHFCHFPh 36% Ex.4 Fluor ®Ph₂CHCF₂H 18% PhSF₃ = phenylsulfur trifluoride; p-CH₃C₆H₄SF₃ =p-methylphenylsulfur trifluoride; r.t. = room temperature; Non = Nosolvent; p-(n-C₇H₁₅)C₆H₄COOH = p-(n-heptyl)benzoic acid; PhSCH₃ =thioanisole; PhSOCH₃ = methyl phenyl sulfoxide; EtOH = ethanol; py =pyridine; PhOC(═S)SCH₃ = O-phenyl S-methyl dithiocarbonate; PhC(═S)OCH₃= O-methyl thiobenzoate.

As shown from the data in Table 5, it has been unexpectedly shown thatthe novel substituted phenylsulfur trifluorides of the invention, thephenylsulfur trifluorides substituted with the alkyl group(s), thehalogen atom(s), and/or the alkyl group(s) having ether linkage, aremuch more effective fluorinating agents than the known and similar PhSF₃(Comparison Example 1) and p-CH₃C₆H₄SF₃ (Comparison Example 2).Furthermore, as seen from the comparison between Examples 55e and 55fand Comparison Examples 3 and 4, the novel substituted phenylsulfurtrifluorides of the invention have high yields and high selectivity influorination compared to conventional fluorinating agents such as DASTand Deoxo-Fluor®. In addition, the present examples illustrate that thenovel compounds of the invention can fluorinate a wide variety of targetcompounds with high yields. Example 54 shows the utility of the presentinvention where a hydrogen atom located at the geminal position of thesulfur atom is replaced with fluorine. In addition, Example 55 alsoillustrates replacement of a hydrogen atom with fluorine.

Examples 56˜63 and Comparison Examples 5˜8 Stability, Safety, andDisposability of the Substituted Phenylsulfur Trifluorides and theConventional Sulfur Trifluorides

Stability, safety, and disposability of the substituted phenylsulfurtrifluorides, IV, IVa,b, XIV˜XVIII, and conventional sulfurtrifluorides, such as DAST, Deoxo-fluor®, phenylsulfur trifluoride(PhSF₃), and p-methylphenylsulfur trifluoride (p-CH₃C₆H₄SF₃) wereexamined by testing for hydrolytic stability. The visual hydrolyticstability test was conducted by adding approximately 10-50 mg of sulfurtrifluoride (“dropwise”) onto a large excess of water in a beaker atroom temperature. Each compound tested was evaluated according to a 1˜10evaluation, where:

-   -   A. reaction when dropped—        -   10=Instant vigorous reaction occurs;        -   5=Instant mild reaction occurs; and        -   1=No instant reaction occurs.    -   B. sound emission when dropped—        -   10=Instant very loud sound occurs;        -   5=Instant mild sound occurs; and        -   1=No sound occurs.    -   C. fume production when dropped—        -   10=Instant much fume produced;        -   5=Instant mild fume produced; and        -   1=No fume produced.

The results are summarized in Table 6. The term “No instant reactionoccurs” means that there was observed no apparent change of the sulfurtrifluoride when the tested material was dropped onto the water.

TABLE 6 Visible Stability in Water of Substituted PhenylsulfurTrifluorides (Formulas IV, IVa, b, and XIV-XVIII), Prior Art Compounds(PhSF₃ and p-CH₃C₆H₄SF₃), and Useful Conventional Fluorinating Agents(DAST and Deoxo-Fluor ®) Fume Sulfur Sound when when Ex. trifluorideReaction when dropped dropped dropped Comparison DAST 10  10 10 Ex. 5Comparison Deoxy-Fluor ® 10  10 10 Ex. 6 Comparison PhSF₃ 5 5 5 Ex. 7Comparison p-CH₃C₆H₄SF₃ 5 5 5 Ex. 8 Ex. 56 IV 1 1 1 (No evident reactionafter 10 min.) Ex. 57 IV (93 mol %) + 1 1 1 IVa (7 mol %) (No evidentreaction after 10 min) Ex. 58 IVb 1 1 1 (Reaction started after ca. 20sec)*¹ Ex. 59 XIV 1 1 1 (Reaction started after ca. 45 sec)*² Ex. 60 XV1 1 1 (Reaction started after ca. 5 min)*³ Ex. 61 XVI   1*⁴ 1 1 Ex. 62XVII   1*⁵ 1 1 Ex. 63 XVIII   1*⁶ 1 1 *¹After ca. 20 sec, the surface ofthe drop started to change milky indicating hydrolysis. *²After ca. 45sec, the surface of the drop started to change milky indicatinghydrolysis. *³After ca. 5 min, the surface of the drop started to changemilky indicating hydrolysis. *⁴After ca. 20 sec, the surface of the droppartially started to changed to change milky indicating hydrolysis, butthe hydrolysis was very slow. *⁵After several seconds, the surface ofthe drop partially started to change milky indicating hydrolysis, butthe hydrolysis was very slow. *⁶After ca. 5 sec, the surface of the droppartially started to change milky indicating hydrolysis, but thehydrolysis was very slow.

Conventional fluorinating agents such as DAST and Deoxo-Fluor® are knownto be extremely sensitive to moisture and easily hydrolyzed andtherefore dangerous when contacted with water (extremely vigorousreaction with water as seen from Table 6). Phenylsulfur trifluoride andp-methylphenylsulfur trifluoride are similar to DAST and Deoxo-Fluor® inthis manner. Contrary to this, substituted phenylsulfur trifluorides ofthe present invention, the phenylsulfur trifluorides substituted withthe alkyl group(s), the halogen atom(s), and/or the alkyl groups havingether linkage, such as IV, IVa,b, and XIV-XVIII, have a relatively highstability to water. This indicates that the substituted phenylsulfurtrifluorides have high stability, storage stability, safety, safehandling, and safe disposability. From the comparison between Examples56˜58 and Comparison Examples 7 and 8, the alkyl group and the halogensubstituents of the present invention unexpectedly and surprisinglyimprove the compounds of the invention's stability to hydrolysis. Fromthe comparison between Example 59 and Comparison Example 7, the alkylgroups having one or more ether linkages have high stability. This alsodemonstrates that the alkyl group, having at least one ether linkage,unexpectedly and surprisingly improves the stability of the phenylsulfurtrifluorides of the invention.

Example 64 Methanolysis Experiment of a 93:7 (mol ratio) Mixture of2,6-dimethyl-4-tert-butylphenylsulfur trifluoride (IV) and2,6-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride (IVa)

A fluoropolymer vessel was charged with 5 g of a 93:7 (mol ratio)mixture of 2,4-dimethyl-4-tert-butylphenylsulfur trifluoride (IV) and2,4-dimethyl-3-chloro-4-tert-butylphenylsulfur trifluoride (IVa) in drybox. 10 mL of anhydrous CH₃OH was slowly added to this mixture.Exothermic reaction occurred during the addition. After addition, thereaction mixture was stirred under N₂ for 30 min. The reaction mixturewas poured into 20 mL of cold aqueous Na₂CO₃ solution and then extractedwith ether. The organic layer was separated and dried over anhydrousMgSO₄, and evaporated to give a light yellow product. Recrystallizationfrom cold hexanes yielded a white solid (4.2 g). ¹H-NMR analysis of thesolid indicated that the solid is a mixture of 92% of compound IV-2 and8% of compound IVa-2.

Compound IV-2: ¹H-NMR (CDCl₃) δ 7.04 (s, 2H, Ar—H), 3.80 (s, 3H,S(O)OCH₃), 2.62 (s, 6H, Ar—CH₃), 1.28 (s, 9H, C(CH₃)₃); GC-Mass 240(M⁺).

Compound IVa-2: ¹H-NMR (CDCl₃) δ 7.12 (s, 1H, Ar—H), 3.83 (s, 3H,S(O)OCH₃), 2.66 (s, 6H, Ar—CH₃), 1.47 (s, 9H, C(CH₃)₃); GC-Mass 276(M⁺), 274 (M⁺).

The formation of these products can be explained by the followingmechanism as shown in the scheme below. The methanolysis consists of twosteps, a first methanolysis followed by a second methanolysis. The firstmethanolysis of compounds, formula IV and IVa, give sulfinyl fluorides,IV-1 and IVa-1, methyl fluoride (CH₃F) and hydrogen fluoride (HF), andthe second methanolysis leads to the final products, IV-2 and IVa-2.

The first methanolysis reaction corresponds to the fluorination reactionof target compounds containing oxygen atoms. This indicates that thefluorination reactions of the target compounds provide sulfinylfluorides such as IV-1 and IVa-1 in addition to the fluorinatinatedproducts. When the sulfinyl fluorides are further hydrolyzed with water,aqueous acidic solution or basic solution, the corresponding sulfinicacids or their salts are formed.

It is understood for purposes of this disclosure, that various changesand modifications may be made to the invention that are well within thescope of the invention. Numerous other changes may be made which willreadily suggest themselves to those skilled in the art which areencompassed in the spirit of the invention disclosed herein and asdefined in the appended claims.

This specification contains numerous citations to references such aspatents, patent applications, and publications. Each is herebyincorporated by reference for all purposes.

1. A process for preparing a compound according to formula (Ia):

comprising reacting a compound of formula (Ia-A) with chlorine (Cl₂) andan alkali metal fluoride;

in which: R^(1a) and R^(1b) are independently a hydrogen atom; a primaryor secondary alkyl group having from one to eight carbon atoms; or aprimary, secondary, or tertiary alkyl group having two to eight carbonatoms and at least one ether linkage; R^(2a′) and R^(2b′) areindependently a hydrogen atom or a halogen atom; and R³ is a hydrogenatom; a primary, secondary, or tertiary alkyl group having from one toeight carbon atoms; or a primary, secondary, or tertiary alkyl grouphaving two to eight carbon atoms and at least one ether linkage; whereinwhen R³ is a hydrogen atom, R^(1a) and R^(1b) are independently aprimary or secondary alkyl group having from one to eight carbon atomsor at least one of R^(1a) and R^(1b) is a primary, secondary, ortertiary alkyl group having two to eight carbon atoms and at least oneether linkage, and wherein, when R³ is a primary alkyl group having oneto eight carbon atoms, at least one of R^(1a) and R^(1b) is a primary orsecondary alkyl group having from one to eight carbon atoms or aprimary, secondary, or tertiary alkyl group having two to eight carbonatoms and at least one ether linkage.
 2. The process of claim 1, whereinthe alkali metal fluoride is potassium fluoride or cesium fluoride. 3.The process of claim 1 further comprising a solvent where the solvent isacetonitrile.
 4. A process for preparing a compound according to formula(II):

comprising reacting a compound of formula (II-A) with chlorine (Cl₂) andan alkali metal fluoride;

in which: R^(1a′) and R^(1b′) are independently a hydrogen atom or aprimary or secondary alkyl group having from one to eight carbon atoms;and R^(3′) is a hydrogen atom, or a primary, secondary, or tertiaryalkyl group having from one to eight carbon atoms; wherein when R^(3′)is a hydrogen atom, R^(1a′) and R^(1b′) are independently a primary orsecondary alkyl group having from one to eight carbon atoms, andwherein, when R^(3′) is a primary alkyl group having one to eight carbonatoms, at least one of R^(1a′) and R^(1b′) is a primary or secondaryalkyl group having from one to eight carbon atoms.
 5. The process ofclaim 4, wherein the alkali metal fluoride is potassium fluoride orcesium fluoride.
 6. The process of claim 4 further comprising a solventwhere the solvent is acetonitrile.
 7. A process for preparing a compoundaccording to formula (Ib):

comprising reacting a compound of formula (Ib-A) with chlorine (Cl₂) andan alkali metal fluoride;

in which R^(3′) is a hydrogen atom, or a primary, secondary, or tertiaryalkyl group having from one to eight carbon atoms; R⁴ is a primary,secondary, or tertiary alkyl group; and R⁵ and R⁶ are independently analkylene group; the number of total carbon atoms of R⁴, R⁵, and R⁶ iseight or less, and m is 0 or
 1. 8. The process of claim 7, wherein thealkali metal fluoride is potassium fluoride or cesium fluoride.
 9. Theprocess of claim 7 further comprising a solvent where the solvent isacetonitrile.
 10. A process for preparing a compound according toformula (Id):

comprising reacting a compound of formula (Ic) with chlorine (Cl₂) andan alkali metal fluoride;

in which R⁷ is a primary, secondary, or tertiary alkyl group having oneto four carbon atoms; and R⁸ is a hydrogen atom or a primary, secondary,or tertiary alkyl group having one to four carbon atoms.
 11. The processof claim 10, wherein the alkali metal fluoride is potassium fluoride orcesium fluoride.
 12. The process of claim 10 further comprising asolvent where the solvent is acetonitrile.